Mu opioid receptor modulators

ABSTRACT

Described herein, inter alia, are compositions and methods for modulating mu opioid receptor activity.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/190,390, filed Jul. 9, 2015, which is incorporated herein byreference in its entirety and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant nos.GM059957, GM106990, DA036246 and DA017204, awarded by the NationalInstitutes of Health. The government has certain rights in theinvention.

BACKGROUND

The use of opioids in therapy dates to the Neolithic, and theireffectiveness for pain treatment, as euphoragens, and theiraddictiveness has made them central to medicine, commerce, and conflictever since. Their addictiveness and potentially lethal side effects,such as respiratory depression, have driven campaigns to improve themsince the 19^(th) century, with the purification of morphine and codeineand the synthesis of heroin. Recently, molecular studies have in factsuggested that the CNS-based analgesia relates to μ opioid receptorsignaling through the G_(i)-protein pathway, while many of thepathophysiologies of the opioid drugs, including respiratory depressionand constipation, is conferred via arrestin pathway signaling.Identifying agonists specific to μ opioid receptors and biased towardthe G_(i)-protein pathway have thus far remained elusive. Disclosedherein, inter alia, are solutions to these and other problems in theart.

BRIEF SUMMARY OF THE INVENTION

In an aspect is provided a compound having the formula:

W is O or S. Ring A is independently substituted or unsubstituted arylor substituted or unsubstituted heteroaryl. Ring B is independentlysubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. L¹ and L² are independently a bond,substituted or unsubstituted (C₁-C₅) alkylene, or substituted orunsubstituted 2 to 5 membered heteroalkylene. R¹ and R² areindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃,—OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted(C₃-C₆) cycloalkyl, or substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. R¹ and R² may optionally be joined to form asubstituted or unsubstituted 3 to 6 membered heterocycloalkyl orsubstituted or unsubstituted 5 to 6 membered heteroaryl. L¹ and R¹ mayoptionally be joined to form a substituted or unsubstituted 4 to 8membered heterocycloalkyl. L¹ and R² may optionally be joined to form asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl. L³ is abond, —O—, —N(R⁶)—, or —CH₂—. R⁵ is hydrogen, —CF₃, —CN, —COOH, —CONH₂,—CHF₂, —CH₂F, substituted or unsubstituted (C₁-C₅) alkyl, or substitutedor unsubstituted 2 to 5 membered heteroalkyl; and R⁶ is hydrogen, —CF₃,—CN, —COOH, —CONH₂, —CHF₂, —CH₂F, substituted or unsubstituted (C₁-C₅)alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl.

In another aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound, as describedherein.

In an aspect is provided a method of treating pain in a subject in needof the treatment, the method including administering an effective amountof a compound as described herein, to the subject. In embodiments, themethod does not include an increased risk of respiratory depression orconstipation.

In an aspect is provided a method of treating opioid overdose in asubject in need of the treatment, the method including administering aneffective amount of a compound as described herein, to the subject.

In another aspect is provided a method of treating addiction in asubject in need of the treatment, the method including administering aneffective amount compound as described herein, to the subject.

In an aspect is provided a method of treating a psychiatric disorder ina subject in need of the treatment, the method including administeringan effective amount of a compound as described herein, to the subject.

In another aspect is provided a method of modulating the activity of anopioid receptor protein, the method including contacting the opioidreceptor protein with an effective amount of a compound as describedherein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Initial docking screen. Single point competition binding assayof 23 candidate molecules against the μOR antagonist radioligand³H-diprenorphine. Each ligand was tested at 20 μM and those showing >25%inhibition were further tested by full displacement curves to determineaffinity; data represent mean±s.e.m. (n=3 measurements).

FIGS. 2A-2H. Predicted binding poses and dose response curves of initialhits from the docking screen against the μ-Opioid Recpetor. All figuresvisualized with Pymol.

FIGS. 3A-3B. Variation of the chiral centers in compound PZM21 resultsin large changes in efficacy and potency. Notably, (S,R)-21 is a morepotent partial agonist of the μOR as compared to (S,S)-21 (PZM21).Structure-activity relationship of compound 12 and 21 stereoisomers withaffinities displayed as pKi values and agonist potency and efficacy in aG_(i/o) Glosensor assay.

FIG. 4. Eight analogs were synthesized to probe the binding orientationof PZM21 and their efficacy as agonists were tested in a G_(i/o)signaling assay. Analogs were compared to a parent reference compound(PZM22) with similar efficacy and potency to PZM21. The covalentcompound PZM29 binds to the μOR:N127C variant irreversibly, as evidencedby wash-resistant inhibition of radioligand binding.

FIG. 5. Signaling properties of PZM21 at the opioid receptors. Displayedare raw luminescence data from a G_(i/o) Glosensor assay. In agonistmode, agonists induce a decrease in luminescence signal while inverseagonists increase signal by decreasing basal signaling. For each opioidreceptor, a prototypical well-characterized agonist and antagonist wereused to validate the assay. In antagonist mode, a competition reactionis performed with 50 nM agonist and an escalating amount of tested drug.Here, true antagonists increase the observed signal, consistent withtheir ability to compete with the agonist but not induce G_(i)signaling.

FIGS. 6A-6B. Biased signaling for PZM21 and compound 12. G_(i/o)signaling assay shows robust μOR agonist activity for PZM21 and compound12 with undetectable β-arrestin2 recruitment in the PathHunter assay.

FIG. 7. Dose-dependent analgesia conferred by PZM21 in a hot-plateassay. Latency of withdrawal to noxious stimuli is shown as percentageof the maximal possible effect (% MPE).

FIG. 8. PZM21 shows no activity in a tail flick assay, unlike previouslycharacterized effects seen with classical opioids.

FIGS. 9A-9B. Analgesic responses measured in the hot-plate assay weresubcategorized into either affective or reflexive behaviors and scoredseparately. Unlike classical opioids like morphine, PZM21 only modulatesthe affective component of pain.

FIG. 10. PZM21 shows reduced constipatory effects as compared tomorphine.

FIG. 11. Unlike morphine and TRV130, PZM21 has no effect on respiratoryfrequency and is statistically similar to vehicle for all times testedafter administration of drug.

FIGS. 12A-12B. Unlike morphine PZM21 does not induce open fieldlocomotion, suggesting decreased activation of dopaminergic rewardcircuits.

FIG. 13. PZM21 does not induce conditioned place preference andtherefore has lower reinforcing activity as compared to morphine. Thismay suggest that PZM21 and analogous molecules have decreased liabilityfor addiction.

FIG. 14. PZM21 does not induce cataleptic behavior.

DETAILED DESCRIPTION

Structure-based optimization led to the identification of an agonist,PZM21, with an EC₅₀ for G_(i/o) activation of 5 nM (K_(i) 1 nM) and withselectivity for μOR activity as compared to the three other opioidreceptors (δ, K, and nociceptin). Consistent with its novel scaffold,PZM21 has unique signaling properties with minimal recruitment ofβ-arrestin2. Compounds disclosed herein in embodiments, reduce theaffective component of pain, without detectably altering reflexivebehaviors. Unlike the respiratory depression observed with morphine, anequianalgesic dose of compounds described herein had little effect onrespiration.

I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclized chain.Examples of saturated hydrocarbon radicals include, but are not limitedto, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds (alkenyl)or triple bonds (alkynyl). An alkenyl may include more than one doublebond and/or one or more triple bonds in addition to the one or moredouble bonds. An alkynyl may include more than one triple bond and/orone or more double bonds in addition to the one or more triple bonds.Examples of unsaturated alkyl groups include, but are not limited to,vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkylattached to the remainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene. The term“alkynylene,” by itself or as part of another substituent, means, unlessotherwise stated, a divalent radical derived from an alkyne.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen andsulfur atoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) maybe placed at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Heteroalkyl is an uncyclized chain. Examples include, but arenot limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. A heteroalkyl moiety mayinclude one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include two optionally different heteroatoms (e.g., O, N, S, Si, orP). A heteroalkyl moiety may include three optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefour optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include five optionally different heteroatoms(e.g., O, N, S, Si, or P). A heteroalkyl moiety may include up to 8optionally different heteroatoms (e.g., O, N, S, Si, or P). The term“heteroalkenyl,” by itself or in combination with another term, means,unless otherwise stated, a heteroalkyl including at least one doublebond. A heteroalkenyl may optionally include more than one double bondand/or one or more triple bonds in additional to the one or more doublebonds. The term “heteroalkynyl,” by itself or in combination withanother term, means, unless otherwise stated, a heteroalkyl including atleast one triple bond. A heteroalkynyl may optionally include more thanone triple bond and/or one or more double bonds in additional to the oneor more triple bonds.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.The term “heteroalkenylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkenyl. The term “heteroalkynylene,” by itself or as part ofanother substituent, means, unless otherwise stated, a divalent radicalderived from heteroalkynyl

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively. The terms “cycloalkenyl” and “cycloalkynyl,” by themselvesor in combination with other terms, mean, unless otherwise stated,cyclic versions of “alkenyl” and “alkynyl,” respectively. The terms“heterocycloalkenyl” and “heterocycloalkynyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “heteroalkenyl” and “heteroalkynyl,” respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl,pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl,oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl,indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl,quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively. Aheteroaryl group substituent may be —O— bonded to a ring heteroatomnitrogen.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different. Individual rings in spirocyclicrings may be substituted or unsubstituted and may have differentsubstituents from other individual rings within a set of spirocyclicrings. Possible substituents for individual rings within spirocyclicrings are the possible substituents for the same ring when not part ofspirocyclic rings (e.g. substituents for cycloalkyl or heterocycloalkylrings). Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylarylene” as an arylene moiety covalently bonded to analkylene moiety (also referred to herein as an alkylene linker). Inembodiments, the alkylarylene group has the formula:

An alkylarylene moiety may be substituted (e.g. with a substituentgroup) on the alkylene moiety or the arylene linker (e.g. at carbons 2,3, 4, or 6) with halogen, oxo, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃—SO₃H, —OSO₃H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl orsubstituted or unsubstituted 2 to 5 membered heteroalkyl). Inembodiments, the alkylarylene is unsubstituted.

Each of the above terms (e.g., “alkyl”, “heteroalkyl”, “cycloalkyl”,“heterocycloalkyl”, “aryl”, and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R′″,and R″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound described herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, ina number ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound described herein includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R′″, and R″″ groups when more than one of these groupsis present.

Substituents for rings (e.g. cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g. a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′— (C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,        —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,        —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃,        —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,        unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,        unsubstituted aryl, unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,            —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,            —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃,            —OCHF₂, unsubstituted alkyl, unsubstituted heteroalkyl,            unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,            unsubstituted aryl, unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,                unsubstituted heteroalkyl, unsubstituted cycloalkyl,                unsubstituted heterocycloalkyl, unsubstituted aryl,                unsubstituted heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, heteroaryl, substituted with at least one                substituent selected from: oxo, halogen, —CF₃, —CN, —OH,                —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,                —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,                —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section, figures, claims, or tables below.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those that are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by 1³C- or 14C-enriched carbonare within the scope of this invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol or number may be used to distinguish eachappearance of that particular R group. For example, where multiple R¹³substituents are present, each R¹³ substituent may be distinguished asR^(13A), R^(13B), R^(13C), R^(13D), etc. (or R^(13.1), R^(13.2),R^(13.3), R^(13.4), etc.), wherein each of R^(13A), R^(13B), R^(13C),R^(13D), etc. (or R^(13.1), R^(13.2), R^(13.3), R^(13.4), etc.) isdefined within the scope of the definition of R¹³ and optionallydifferently.

A “detectable moiety” as used herein refers to a moiety that can becovalently or noncovalently attached to a compound or biomolecule thatcan be detected for instance, using techniques known in the art. Inembodiments, the detectable moiety is covalently attached. Thedetectable moiety may provide for imaging of the attached compound orbiomolecule. The detectable moiety may indicate the contacting betweentwo compounds. Exemplary detectable moieties are fluorophores,antibodies, reactive dies, radio-labeled moieties, magnetic contrastagents, and quantum dots. Exemplary fluorophores include fluorescein,rhodamine, GFP, coumarin, FITC, Alexa fluor, Cy3, Cy5, BODIPY, andcyanine dyes. Exemplary radionuclides include Fluorine-18, Gallium-68,and Copper-64. Exemplary magnetic contrast agents include gadolinium,iron oxide and iron platinum, and manganese.

Description of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Non-limiting examples of such salts include hydrochlorides,hydrobromides, phosphates, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g.,(+)-tartrates, (−)-tartrates, or mixtures thereof including racemicmixtures), succinates, benzoates, and salts with amino acids such asglutamic acid, and quaternary ammonium salts (e.g. methyl iodide, ethyliodide, and the like). These salts may be prepared by methods known tothose skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Prodrugs of the compounds described herein may be convertedin vivo after administration. Additionally, prodrugs can be converted tothe compounds of the present invention by chemical or biochemicalmethods in an ex vivo environment, such as, for example, when contactedwith a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the compounds described herein without causing asignificant adverse toxicological effect on the patient. Non-limitingexamples of pharmaceutically acceptable excipients include water, NaCl,normal saline solutions, lactated Ringer's, normal sucrose, normalglucose, binders, fillers, disintegrants, lubricants, coatings,sweeteners, flavors, salt solutions (such as Ringer's solution),alcohols, oils, gelatins, carbohydrates such as lactose, amylose orstarch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine,and colors, and the like. Such preparations can be sterilized and, ifdesired, mixed with auxiliary agents such as lubricants, preservatives,stabilizers, wetting agents, emulsifiers, salts for influencing osmoticpressure, buffers, coloring, and/or aromatic substances and the likethat do not deleteriously react with the compounds described herein. Oneof skill in the art will recognize that other pharmaceutical excipientsare useful in combination with the compounds described herein.

Pharmaceutical compositions may include compositions wherein the activeingredient (e.g. compounds described herein) is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. When administered in methods to treat a disease, suchcompositions will contain an amount of active ingredient effective toachieve the desired result, e.g., modulating the activity of a targetmolecule, and/or reducing, eliminating, or slowing the progression ofdisease symptoms.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated, kind of concurrent treatment, complications from thedisease being treated or other health-related problems. Othertherapeutic regimens or agents can be used in conjunction with themethods and compounds described herein. Adjustment and manipulation ofestablished dosages (e.g., frequency and duration) are well within theability of those skilled in the art.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

A “mu opioid receptor modulator” or “mu opioid receptor compound” or “Popioid receptor modulator” refers to a compound (e.g. compoundsdescribed herein) that reduce the activity of opioid receptor whencompared to a control, such as absence of the compound or a compoundwith known inactivity.

A“specific,” “specifically”, “specificity”, or the like of a compoundrefers to the compound's ability to discriminate between particularmolecular targets to a significantly greater extent than other proteinsin the cell (e.g. a compound having specificity towards μ opioidreceptor (“μ opioid receptor—specific compound” or a compound includinga “μ opioid receptor—specific moiety”) binds to μ opioid receptorwhereas the same compound displays little-to-no binding to other opioidreceptors such as kappa opioid receptor or delta opioid receptor, ornociceptin receptor). A “μ opioid receptor −specific compound” refers toa compound (e.g. compounds described herein) having specificity towardsμ opioid receptor (e.g., over one or more other opioid receptors).

The terms “selective,” or “selectivity” or the like of a compound refersto the compound's ability to cause a particular action in a particularmolecular target (e.g. a compound having selectivity toward opioidreceptor would inhibit only opioid receptor). A “μ opioid receptor−selective compound” or a compound including a “μ opioid receptor−selective moiety” refers to a compound (e.g. compounds describedherein) having selectivity towards opioid receptor.

The terms “polypeptide,” “peptide” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues,wherein the polymer may optionally be conjugated to a moiety that doesnot consist of amino acids. The terms apply to amino acid polymers inwhich one or more amino acid residue is an artificial chemical mimeticof a corresponding naturally occurring amino acid, as well as tonaturally occurring amino acid polymers and non-naturally occurringamino acid polymer.

A polypeptide, or a cell is “recombinant” when it is artificial orengineered, or derived from or contains an artificial or engineeredprotein or nucleic acid (e.g. non-natural or not wild type). Forexample, a polynucleotide that is inserted into a vector or any otherheterologous location, e.g., in a genome of a recombinant organism, suchthat it is not associated with nucleotide sequences that normally flankthe polynucleotide as it is found in nature is a recombinantpolynucleotide. A protein expressed in vitro or in vivo from arecombinant polynucleotide is an example of a recombinant polypeptide.Likewise, a polynucleotide sequence that does not appear in nature, forexample a variant of a naturally occurring gene, is recombinant.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents that can be producedin the reaction mixture.

The term “contacting” may include allowing two species to react,interact, or physically touch, wherein the two species may be a compoundas described herein and a protein or enzyme. In some embodimentscontacting includes allowing a compound described herein to interactwith a protein or enzyme that is involved in a signaling pathway.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein-activator interaction meanspositively affecting (e.g. increasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the activator. In embodiments inhibition refers meanspositively affecting (e.g. increasing) the concentration or levels ofthe protein relative to the concentration or level of the protein in theabsence of the activator. In embodiments, activation refers to anincrease in the activity of a particular protein target (mu opioidreceptor). Thus, activation includes, at least in part, partially ortotally increasing stimulation or activation, or activating,sensitizing, or up-regulating signal transduction or enzymatic activityor the amount of a protein. In embodiments, activation refers to anincrease of activity of a target protein resulting from a directinteraction (e.g. an activator binds to the target protein). Inembodiments, activation refers to an increase of activity of a targetprotein from an indirect interaction (e.g. an activator binds to aprotein that inhibits the target protein, thereby causing target proteinactivation).

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g. decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. In embodiments inhibition refers meansnegatively affecting (e.g. decreasing) the concentration or levels ofthe protein relative to the concentration or level of the protein in theabsence of the inhibitor. In embodiments inhibition refers to reductionof a disease or symptoms of disease. In embodiments, inhibition refersto a reduction in the activity of a particular protein target. Thus,inhibition includes, at least in part, partially or totally blockingstimulation, decreasing, preventing, or delaying activation, orinactivating, desensitizing, or down-regulating signal transduction orenzymatic activity or the amount of a protein. In embodiments,inhibition refers to a reduction of activity of a target proteinresulting from a direct interaction (e.g. an inhibitor binds to thetarget protein). In embodiments, inhibition refers to a reduction ofactivity of a target protein from an indirect interaction (e.g. aninhibitor binds to a protein that activates the target protein, therebypreventing target protein activation).

Opioid receptors are a group of inhibitory G-protein coupled receptorsthat bind opioids (e.g., endogenous opioids are dynorphins, enkephalins,endorphins, endomorphins, and nociception).

The terms “μ opioid receptor” and “mu opioid receptor” or “MOR” refer toa subtype of opioid receptor and is used according to its common,ordinary meaning. “μ opioid receptor” refers to proteins of the same orsimilar names, homologs, isoforms, and functional fragments thereof, solong as such fragments retain μ opioid receptor activity. The termincludes any recombinant or naturally-occurring form of μ opioidreceptor, or variants thereof that maintain opioid receptor activity(e.g. within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%activity compared to wildtype opioid receptor). In embodiments, the μopioid receptor protein encoded by the OPRM1 gene has the amino acidsequence set forth in RefSeq (mRNA) NM_000914, NM_001008503,NM_001008504, NM_001008505, NM_001145279, NM_001145280, NM_001145281,NM_001145282, NM_001145283, NM_001145284, NM_001145285, NM_001145286,NM_001145287, NM_001285522, NM_001285523, NM_001285524, NM_001285526,NM_001285527, or NM_001285528. In embodiments, the μ opioid receptorprotein encoded by the OPRM1 gene has the amino acid sequence set forthin RefSeq (protein) NP_000905.3, NP_001008503.2, NP_001008504.2,NP_001008505.2, NP_001138751.1, NP_001138752.1, NP_001138753.1,NP_001138754.1, NP_001138755.1, NP_001138756.1, NP_001138757.1,NP_001138758.1, NP_001138759.1, NP_001272452.1, NP_001272453.1,NP_001272455.1, NP_001272456.1, or NP_001272457.1.

In embodiments, the μ opioid receptor protein encoded by the OPRM1 genehas the amino acid sequence set forth in Entrez 4988, UniProt P35372,RefSeq (mRNA) NM_000914, or RefSeq (protein) NP_000905. In embodiments,the μ opioid receptor protein is a human protein. In embodiments, the μopioid receptor protein is a wildtype protein. In embodiments, the μopioid receptor protein mutant protein. In embodiments, the μ opioidreceptor protein corresponds to GI: 117940060. In embodiments, the μopioid receptor protein corresponds to NP_000905.3. In embodiments, theμ opioid receptor protein corresponds to GI:550822366. In embodiments,the μ opioid receptor protein corresponds to NM_000914.4.

The term “expression” includes any step involved in the production ofthe polypeptide including, but not limited to, transcription,post-transcriptional modification, translation, post-translationalmodification, and secretion. Expression can be detected usingconventional techniques for detecting protein (e.g., ELISA, Westernblotting, flow cytometry, immunofluorescence, immunohistochemistry,etc.).

The terms “disease” or “condition” refer to a state of being or healthstatus of a patient or subject capable of being treated with thecompounds or methods provided herein. The disease may be pain, such asfor example, nociceptive pain, inflammatory pain which is associatedwith tissue damage and/or the infiltration of immune cells, orpathological pain, for example a disease state caused by damage to thenervous system (neuropathic pain) or by its abnormal function(dysfunctional pain (e.g., fibromyalgia, irritable bowel syndrome,tension type headache)). In embodiments, the pain may be acute pain. Inembodiments, the pain may be chronic pain. In embodiments, thenociceptive pain may be associated with ischemia. In embodiments, thenociceptive pain may be associated with inflammation. In embodiments,the nociceptive pain may be deep somatic pain (e.g., due to damage toligaments, tendons, bonds, blood vessels, fasciae, or muscles). Inembodiments, the nociceptive pain may be associated with skin. Inembodiments, the nociceptive pain may be associated with a burn. Inembodiments, the pain may be psychogenic (e.g., associated withheadache, back pain, stomach pain). In embodiments, the pain may bebreakthrough pain. In embodiments, the pain may be breakthrough pain nottreated by standard pain management. In embodiments, the pain may bebreakthrough pain associated with cancer. In embodiments, the pain maybe a pain capable of being treated with an opioid. The disease may be adrug addiction (e.g., addiction to an opioid, tobacco, narcotic, heroin,morphine, opiate, alcohol, cocaine, amphetamine, methamphetamine, MDMA,GHB, LSD, PCP, hydrocodone, oxycodone, fentanyl, or marijuana,methadone, hydromorphone, or a derivative thereof). The disease may beopioid poisoning (e.g., overdose), for example poisoning with heroin,fentanyl, or morphine.

The terms “treating”, or “treatment” refer to any indicia of success inthe therapy or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment of symptoms can be based on objective or subjectiveparameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. The termstreatment, therapy and the like include, but are not limited to, methodsand manipulations to produce beneficial changes in a recipient's healthstatus. The changes can be either subjective or objective and can relateto features such as symptoms or signs of the disease, disorder orcondition being treated. For example, if the patient notes decreasedpain, then successful treatment of pain has occurred. The term“treating” and conjugations thereof, include prevention of an injury,pathology, condition, or disease.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a pharmaceutical composition as provided herein.Non-limiting examples include humans, other mammals, bovines, rats,mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammaliananimals. In some embodiments, a patient is human.

A “effective amount” is an amount sufficient for a compound toaccomplish a stated purpose relative to the absence of the compound(e.g. achieve the effect for which it is administered, treat a disease,reduce enzyme activity, increase enzyme activity, reduce a signalingpathway, or reduce one or more symptoms of a disease or condition). Anexample of an “effective amount” is an amount sufficient to contributeto the treatment, prevention, or reduction of a symptom or symptoms of adisease, which could also be referred to as a “therapeutically effectiveamount.” A “reduction” of a symptom or symptoms (and grammaticalequivalents of this phrase) means decreasing of the severity orfrequency of the symptom(s), or elimination of the symptom(s). A“prophylactically effective amount” of a drug is an amount of a drugthat, when administered to a subject, will have the intendedprophylactic effect, e.g., preventing or delaying the onset (orreoccurrence) of an injury, disease, pathology or condition, or reducingthe likelihood of the onset (or reoccurrence) of an injury, disease,pathology, or condition, or their symptoms. The full prophylactic effectdoes not necessarily occur by administration of one dose, and may occuronly after administration of a series of doses. Thus, a prophylacticallyeffective amount may be administered in one or more administrations. An“activity decreasing amount,” as used herein, refers to an amount ofantagonist required to decrease the activity of an enzyme relative tothe absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt thefunction of an enzyme or protein relative to the absence of theantagonist. The exact amounts will depend on the purpose of thetreatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached. Dosage amounts and intervals can be adjusted individually toprovide levels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,intraperitoneal, intramuscular, intralesional, intrathecal, intranasalor subcutaneous administration, or the implantation of a slow-releasedevice, e.g., a mini-osmotic pump, to a subject. Administration is byany route, including parenteral and transmucosal (e.g., buccal,sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal)compatible with the preparation. Parenteral administration includes,e.g., intravenous, intramuscular, intra-arteriole, intradermal,subcutaneous, intraperitoneal, intraventricular, and intracranial. Othermodes of delivery include, but are not limited to, the use of liposomalformulations, intravenous infusion, transdermal patches, etc.

“Co-administer” it is meant that a composition described herein isadministered at the same time, just prior to, or just after theadministration of one or more additional therapies. The compounds of theinvention can be administered alone or can be coadministered to thepatient. Coadministration is meant to include simultaneous or sequentialadministration of the compounds individually or in combination (morethan one compound). Thus, the preparations can also be combined, whendesired, with other active substances (e.g. to reduce metabolicdegradation). The compositions of the present invention can be deliveredtransdermally, by a topical route, or formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols.

A “cell” as used herein, refers to a cell carrying out metabolic orother function sufficient to preserve or replicate its genomic DNA. Acell can be identified by well-known methods in the art including, forexample, presence of an intact membrane, staining by a particular dye,ability to produce progeny or, in the case of a gamete, ability tocombine with a second gamete to produce a viable offspring. Cells mayinclude prokaryotic and eukaroytic cells. Prokaryotic cells include butare not limited to bacteria. Eukaryotic cells include but are notlimited to yeast cells and cells derived from plants and animals, forexample mammalian, insect (e.g., spodoptera) and human cells. Cells maybe useful when they are naturally nonadherent or have been treated notto adhere to surfaces, for example by trypsinization.

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity of a protein in the absenceof a compound as described herein (including embodiments and examples).

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule orthe physical state of the target of the molecule relative to the absenceof the modulator. In some embodiments, a μ opioid receptor diseasemodulator is a compound that reduces the severity of one or moresymptoms of a disease associated with μ opioid receptor (e.g. pain ordrug addiction). A μ opioid receptor modulator is a compound thatincreases or decreases the activity or function or level of activity orlevel of function of μ opioid receptor or level of μ opioid receptor ina particular physical state.

The term “modulate” is used in accordance with its plain ordinarymeaning and refers to the act of changing or varying one or moreproperties. “Modulation” refers to the process of changing or varyingone or more properties. For example, as applied to the effects of amodulator on a target protein, to modulate means to change by increasingor decreasing a property or function of the target molecule or theamount of the target molecule.

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g. aprotein associated disease, a pain associated with μ opioid receptoractivity, μ opioid receptor associated pain, μ opioid receptorassociated disease, μ opioid receptor associated drug addiction. Forexample, a pain associated with μ opioid receptor activity or functionmay be a pain that results (entirely or partially) from aberrant μopioid receptor function (e.g. enzyme activity, protein-proteininteraction, signaling pathway) or a pain wherein a particular symptomof the disease is caused (entirely or partially) by aberrant μ opioidreceptor activity or function. As used herein, what is described asbeing associated with a disease, if a causative agent, could be a targetfor treatment of the disease. For example, a pain associated with μopioid receptor activity or function or a μ opioid receptor associatedpain, may be treated with a μ opioid receptor modulator or μ opioidreceptor activator, in the instance where decreased μ opioid receptoractivity or function (e.g. signaling pathway activity) causes the pain.For example, a drug addiction associated with increased μ opioidreceptor activity or function or a μ opioid receptor associatedaddiction, may be treated with a μ opioid receptor modulator or μ opioidreceptor inhibitor, in the instance where increased (e.g., due to theaddictive drug) μ opioid receptor activity or function (e.g. signalingpathway activity) causes the drug addiction.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity or protein function, aberrant refersto activity or function that is greater or less than a normal control orthe average of normal non-diseased control samples. Aberrant activitymay refer to an amount of activity that results in a disease, whereinreturning the aberrant activity to a normal or non-disease-associatedamount (e.g. by administering a compound or using a method as describedherein), results in reduction of the disease or one or more diseasesymptoms.

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propogated to other signaling pathway components. Forexample, binding of a μ opioid receptor with a compound as describedherein may result in a change in one or more protein-proteininteractions of the opioid receptor or interactions between the μ opioidreceptor and downstream effectors or signaling pathway components,resulting in changes in cell function.

II. Compounds

In an aspect is provided herein, a compound having the formula:

The symbol W is O or S. Ring A is independently substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl. Ring B is independently substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. L¹and L² are independently a bond, substituted or unsubstituted alkylene,or substituted or unsubstituted heteroalkylene. R⁵ is hydrogen, —CF₃,—CN, —COOH, —CONH₂, —CHF₂, —CH₂F, substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

R¹ and R² are independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, or substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. R¹ and R² may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl or substituted orunsubstituted heteroaryl. L¹ and R¹ may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl. L¹ and R² may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl.

L³ is a bond, —O—, —N(R⁶)—, —CH(R⁶)—, or —CH₂—. R⁶ is

hydrogen, —CF₃, —CN, —COOH, —CONH₂, —CHF₂, —CH₂F, substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl. Inembodiments, L³ is a bond, substituted or unsubstituted alkylene, orsubstituted or unsubstituted heteroalkylene. In embodiments, Ring A isindependently substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl. In embodiments, L¹ and L² are independently abond, substituted or unsubstituted alkylene, or substituted orunsubstituted 2 to 5 membered heteroalkylene. In embodiments, R⁶ ishydrogen, —CF₃, —CN, —COOH, —CONH₂, —CHF₂, —CH₂F, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R⁶ is hydrogen. In embodiments, R⁶is an unsubstituted methyl.

In embodiments, L¹ and L² are independently a bond, substituted orunsubstituted (C₁-C₅) alkylene, or substituted or unsubstituted 2 to 5membered heteroalkylene. In embodiments, L and L² are independently abond, substituted or unsubstituted (C₂-C₅) alkylene, or substituted orunsubstituted 2 to 5 membered heteroalkylene.

In embodiments, R¹ and R² are independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹ and R² may optionally be joined to form a substituted orunsubstituted 3 to 6 membered heterocycloalkyl or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, L¹ and R¹ mayoptionally be joined to form a substituted or unsubstituted 4 to 8membered heterocycloalkyl. In embodiments, L¹ and R² may optionally bejoined to form a substituted or unsubstituted 4 to 8 memberedheterocycloalkyl.

In embodiments, R⁵ is hydrogen, —CF₃, —CN, —COOH, —CONH₂, —CHF₂, —CH₂F,substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl. In embodiments, R⁵ ishydrogen. In embodiments, R⁵ is an unsubstituted methyl. In embodiments,R⁵ is an unsubstituted ethyl. In embodiments, R⁵ is an unsubstitutedisopropyl. In embodiments, R⁵ is an unsubstituted propyl. Inembodiments, R⁵ is an unsubstituted t-butyl. In embodiments, R⁵ is anunsubstituted ethenyl. In embodiments, R⁵ is an unsubstituted propenyl.

In embodiments, R⁵ is independently hydrogen, oxo,

halogen, —CX⁵ ₃, —CHX⁵ ₂, —OCH₂X⁵, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵ ₃, —OCHX⁵ ₂,R⁴²-substituted or unsubstituted alkyl, R⁴²-substituted or unsubstitutedheteroalkyl, R⁴²-substituted or unsubstituted cycloalkyl, R⁴²substituted or unsubstituted heterocycloalkyl, R⁴²-substituted orunsubstituted aryl, or R⁴²-substituted or unsubstituted heteroaryl. X⁵is independently halogen. In embodiments, X⁵ is independently F or Cl.

R⁴² is independently oxo,

halogen, —CX⁴² ₃, —CHX⁴² ₂, —OCH₂X⁴², —OCHX⁴² ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁴² ₃, —OCHX⁴² ₂, R⁴³-substituted or unsubstituted alkyl,R⁴³-substituted or unsubstituted heteroalkyl, R⁴³-substituted orunsubstituted cycloalkyl, R⁴³-substituted or unsubstitutedheterocycloalkyl, R⁴³-substituted or unsubstituted aryl, orR⁴³-substituted or unsubstituted heteroaryl. X⁴² is independentlyhalogen. In embodiments, X⁴² is independently F or Cl.

R⁴³ is independently oxo,

halogen, —CX⁴³ ₃, —CHX⁴³ ₂, —OCH₂X⁴³, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴³ ₃, —OCHX⁴³ ₂,R⁴⁴-substituted or unsubstituted alkyl, R⁴⁴-substituted or unsubstitutedheteroalkyl, R⁴⁴-substituted or unsubstituted cycloalkyl,R⁴⁴-substituted or unsubstituted heterocycloalkyl, R⁴⁴-substituted orunsubstituted aryl, or R⁴⁴-substituted or unsubstituted heteroaryl. X⁴³is independently halogen. In embodiments, X⁴³ is independently F or Cl.

In embodiments, W is O. In embodiments, W is S. Ring A is independentlysubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl; Ring B is independently substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. L¹and L² are independently a bond, substituted or unsubstituted (C₁-C₅)alkylene, or substituted or unsubstituted 2 to 5 memberedheteroalkylene.

R¹ and R² are independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl; R¹ andR² may optionally be joined to form a substituted or unsubstituted 3 to6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6membered heteroaryl.

L¹ and R¹ may optionally be joined to form a substituted orunsubstituted 4 to 8 membered heterocycloalkyl. L¹ and R² may optionallybe joined to form a substituted or unsubstituted 4 to 8 memberedheterocycloalkyl. L³ is a bond, —O—, —N(R⁶)—, or —CH₂—. R⁵ is hydrogen,—CF₃, —CN, —COOH, —CONH₂, —CHF₂, —CH₂F, substituted or unsubstituted(C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5 memberedheteroalkyl. R⁶ is hydrogen, —CF₃, —CN, —COOH, —CONH₂, —CHF₂, —CH₂F,substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl. In embodiments, L³ is a bond,—N(R⁶)—, or —O—. In embodiments, L³ is a bond, —NH—, or —O—.

In embodiments, the compound has the formula:

R¹, R², R⁵, L¹, L², L³, W, Ring A, and Ring B are as described herein(e.g., including in formula I, and embodiments).

In embodiments, the compound has the formula:

R¹, R², R⁵, L¹, L², L³, W, Ring A, and Ring B are as described herein(e.g., including in formula I, and embodiments thereof).

In embodiments, Ring A is substituted or unsubstituted (C₆-C₁₀) aryl orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, Ring A is substituted or unsubstituted (C₆-C₁₀) aryl orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Ring A may besubstituted or unsubstituted (C₆-C₁₀) aryl. Ring A may be substituted orunsubstituted phenyl. Ring A may be substituted or unsubstitutednapthyl. Ring A may be substituted or unsubstituted 5 to 10 memberedheteroaryl. Ring A may be substituted or unsubstituted 5 to 6 memberedheteroaryl. Ring A may be substituted or unsubstituted thienyl. Ring Amay be substituted or unsubstituted furanyl. Ring A may be substitutedor unsubstituted pyrrolyl. Ring A may be substituted or unsubstitutedimidazolyl. Ring A may be substituted or unsubstituted pyrazolyl. Ring Amay be substituted or unsubstituted oxazolyl. Ring A may be substitutedor unsubstituted isoxazolyl. Ring A may be substituted or unsubstitutedthaizolyl. Ring A may be substituted or unsubstituted pyridinyl. Ring Amay be substituted or unsubstituted pyridyl. Ring A may be substitutedor unsubstituted pyrazinyl. Ring A may be substituted or unsubstitutedpyrimidinyl. Ring A may be substituted or unsubstituted pyridazinyl.Ring A may be substituted or unsubstituted 1,2,3-triazinyl. Ring A maybe substituted or unsubstituted 1,2,4-triazinyl. Ring A may besubstituted or unsubstituted 1,3,5-triazinyl. In embodiments, Ring A issubstituted (C₆-C₁₀) aryl or substituted 5 to 10 membered heteroaryl. Inembodiments, Ring A is substituted (C₆-C₁₀) aryl or substituted 5 to 10membered heteroaryl. Ring A may be substituted (C₆-C₁₀) aryl. Ring A maybe substituted phenyl. Ring A may be substituted napthyl. Ring A may besubstituted 5 to 10 membered heteroaryl. Ring A may be substituted 5 to6 membered heteroaryl. Ring A may be substituted thienyl. Ring A may besubstituted furanyl. Ring A may be substituted pyrrolyl. Ring A may besubstituted imidazolyl. Ring A may be substituted pyrazolyl. Ring A maybe substituted oxazolyl. Ring A may be substituted isoxazolyl. Ring Amay be substituted thaizolyl. Ring A may be substituted pyridinyl. RingA may be substituted pyridyl. Ring A may be substituted pyrazinyl. RingA may be substituted pyrimidinyl. Ring A may be substituted pyridazinyl.Ring A may be substituted 1,2,3-triazinyl. Ring A may be substituted1,2,4-triazinyl. Ring A may be substituted 1,3,5-triazinyl. Inembodiments, Ring A is unsubstituted (C₆-C₁₀) aryl or unsubstituted 5 to10 membered heteroaryl. In embodiments, Ring A is unsubstituted (C₆-C₁₀)aryl or unsubstituted 5 to 10 membered heteroaryl. Ring A may beunsubstituted (C₆-C₁₀) aryl. Ring A may be unsubstituted phenyl. Ring Amay be unsubstituted napthyl. Ring A may be unsubstituted 5 to 10membered heteroaryl. Ring A may be unsubstituted 5 to 6 memberedheteroaryl.

Ring A may be unsubstituted thienyl. Ring A may be unsubstitutedfuranyl. Ring A may be unsubstituted pyrrolyl. Ring A may beunsubstituted imidazolyl. Ring A may be unsubstituted pyrazolyl. Ring Amay be unsubstituted oxazolyl. Ring A may be unsubstituted isoxazolyl.Ring A may be unsubstituted thaizolyl. Ring A may be unsubstitutedpyridinyl. Ring A may be unsubstituted pyridyl. Ring A may beunsubstituted pyrazinyl. Ring A may be unsubstituted pyrimidinyl. Ring Amay be unsubstituted pyridazinyl. Ring A may be unsubstituted1,2,3-triazinyl. Ring A may be unsubstituted 1,2,4-triazinyl. Ring A maybe unsubstituted 1,3,5-triazinyl.

In embodiments, Ring A is R³-substituted or unsubstituted (C₆-C₁₀) arylor R³-substituted or unsubstituted 5 to 10 membered heteroaryl. Ring Amay be R³-substituted or unsubstituted (C₆-C₁₀) aryl. Ring A may beR³-substituted or unsubstituted phenyl. Ring A may be R³-substituted orunsubstituted napthyl. Ring A may be R³-substituted or unsubstituted 5to 10 membered heteroaryl. Ring A may be R³-substituted or unsubstituted5 to 6 membered heteroaryl. Ring A may be R³-substituted orunsubstituted thienyl. Ring A may be R³-substituted or unsubstitutedfuranyl. Ring A may be R³-substituted or unsubstituted pyrrolyl. Ring Amay be R³-substituted or unsubstituted imidazolyl. Ring A may beR³-substituted or unsubstituted pyrazolyl. Ring A may be R³-substitutedor unsubstituted oxazolyl. Ring A may be R³-substituted or unsubstitutedisoxazolyl. Ring A may be R³-substituted or unsubstituted thaizolyl.Ring A may be R³-substituted or unsubstituted pyridinyl. Ring A may beR³-substituted or unsubstituted pyridyl. Ring A may be R³-substituted orunsubstituted pyrazinyl. Ring A may be R³-substituted or unsubstitutedpyrimidinyl. Ring A may be R³-substituted or unsubstituted pyridazinyl.Ring A may be R³-substituted or unsubstituted 1,2,3-triazinyl. Ring Amay be R³-substituted or unsubstituted 1,2,4-triazinyl. Ring A may beR³-substituted or unsubstituted 1,3,5-triazinyl. In embodiments, Ring Ais R³-substituted (C₆-C₁₀) aryl or R³ substituted 5 to 10 memberedheteroaryl. Ring A may be R³-substituted (C₆-C₁₀) aryl. Ring A may beR³-substituted phenyl. Ring A may be R³-substituted napthyl. Ring A maybe R³-substituted 5 to 10 membered heteroaryl. Ring A may beR³-substituted 5 to 6 membered heteroaryl. Ring A may be R³-substitutedthienyl. Ring A may be R³-substituted furanyl. Ring A may beR³-substituted pyrrolyl. Ring A may be R³-substituted imidazolyl. Ring Amay be R³-substituted pyrazolyl. Ring A may be R³-substituted oxazolyl.Ring A may be R³-substituted isoxazolyl. Ring A may be R³-substitutedthaizolyl. Ring A may be R³-substituted pyridinyl. Ring A may beR³-substituted pyridyl. Ring A may be R³-substituted pyrazinyl. Ring Amay be R³-substituted pyrimidinyl. Ring A may be R³-substitutedpyridazinyl. Ring A may be R³-substituted 1,2,3-triazinyl. Ring A may beR³-substituted 1,2,4-triazinyl. Ring A may be R³-substituted1,3,5-triazinyl. Ring A may be substituted with one R³. Ring A may besubstituted with two optionally different R³ substituents. Ring A may besubstituted with three optionally different R³ substituents. Ring A maybe substituted with four optionally different R³ substituents. Ring Amay be substituted with five optionally different R³ substituents. RingA may be substituted with six optionally different R³ substituents. RingA may be substituted with seven optionally different R³ substituents.Ring A may be substituted with eight optionally different R³substituents. Ring A may be substituted with nine optionally differentR³ substituents. Ring A may be substituted with ten optionally differentR³ substituents.

R³ is independently hydrogen, halogen, —CX₃, —CN, —SO_(n)R¹⁰,—SO_(v)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸, —NHC═(O)NR⁷R⁸,—N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰,—NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂, —CH₂X, —OCX₃, —OCHX₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. Where multiple R³ substituentsare present, the multiple R³ substituents may be referred to as R^(3A),R^(3B), R^(3C), R^(3D) and R^(3E) as set forth, for example, in formulaeprovided herein such as Formulae (IV), (IVa) and (IVb). In embodimentswhere Ring A is a six-membered cyclic substituent, R^(3A) is at the paraposition, R^(3B) and R^(3C) are at the meta positions and R^(3D) andR^(3E) are at the ortho positions, wherein R^(3D) is adjacent to R^(3B)and R^(3E) is adjacent to R^(3C). Two adjacent R³ substituents (e.g.,R^(3B) and R^(3D), R^(3B) and R^(3A), R^(3A) and R^(3C), R^(3C) andR^(3E)) may optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R³ is independently hydrogen, oxo,

halogen, —CX³ ₃, —CHX³ ₂, —OCH₂X³, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³ ₃, —OCHX³ ₂,R³⁶-substituted or unsubstituted alkyl, R³⁶-substituted or unsubstitutedheteroalkyl, R³⁶-substituted or unsubstituted cycloalkyl,R³⁶-substituted or unsubstituted heterocycloalkyl, R³⁶-substituted orunsubstituted aryl, or R³⁶-substituted or unsubstituted heteroaryl. X³is independently halogen. In embodiments, X³ is independently F or Cl.

R³⁶ is independently oxo,

halogen, —CX³⁶ ₃, —CHX³⁶ ₂, —OCH₂X³⁶, —OCHX³⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX³⁶ ₃, —OCHX³⁶ ₂, R³⁷-substituted or unsubstituted alkyl,R³⁷-substituted or unsubstituted heteroalkyl, R³⁷-substituted orunsubstituted cycloalkyl, R³⁷-substituted or unsubstitutedheterocycloalkyl, R³⁷-substituted or unsubstituted aryl, orR³⁷-substituted or unsubstituted heteroaryl. X³⁶ is independentlyhalogen. In embodiments, X³⁶ is independently F or Cl.

R³⁷ is independently oxo,

halogen, —CX³⁷ ₃, —CHX³⁷ ₂, —OCH₂X³⁷, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³⁷ ₃, —OCHX³⁷ ₂,R³⁸-substituted or unsubstituted alkyl, R³⁸-substituted or unsubstitutedheteroalkyl, R³⁸-substituted or unsubstituted cycloalkyl, R³⁸substituted or unsubstituted heterocycloalkyl, R³⁸-substituted orunsubstituted aryl, or R³⁸-substituted or unsubstituted heteroaryl. X³⁷is independently halogen. In embodiments, X³⁷ is independently F or Cl.

R³ may independently be halogen, —CX₃, —CN, —SO_(n)R¹⁰, —SO_(v)NR⁷R⁸,—NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸, —NHC═(O)NR⁷R⁸, —N(O)_(m), —NR⁷R⁸,—C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹,—NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂, —CH₂X, —OCX₃, —OCHX₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R³ is hydrogen. Inembodiments, R³ is independently halogen. In embodiments, R³ is —CX₃. Inembodiments, R³ is —CN. In embodiments, R³ is —SO_(n)R¹⁰. Inembodiments, R³ is —SO_(v)NR⁷R⁸. In embodiments, R³ is —NHNR⁷R⁸. Inembodiments, R³ is —ONR⁷R⁸. In embodiments, R³ is —NHC═(O)NHNR⁷R⁸. Inembodiments, R³ is —NHC═(O)NR⁷R⁸. In embodiments, R³ is —N(O)_(m). Inembodiments, R³ is —NR⁷R⁸. In embodiments, R³ is —C(O)R⁹. Inembodiments, R³ is —C(O)—OR⁹. In embodiments, R³ is —C(O)NR⁷R⁸. Inembodiments, R³ is —OR¹⁰. In embodiments, R³ is —NR⁷SO₂R¹⁰. Inembodiments, R³ is —NR⁷C═(O)R⁹. In embodiments, R³ is —NR⁷C(O)OR⁹. Inembodiments, R³ is —NR⁷OR⁹. In embodiments, R³ is —CHX₂. In embodiments,R³ is —CH₂X. In embodiments, R³ is —OCX₃. In embodiments, R³ is —OCHX₂.In embodiments, R³ is substituted or unsubstituted alkyl. Inembodiments, R³ is substituted or unsubstituted heteroalkyl. Inembodiments, R³ is substituted or unsubstituted cycloalkyl. Inembodiments, R³ is substituted or unsubstituted heterocycloalkyl. Inembodiments, R³ is substituted or unsubstituted aryl. In embodiments, R³is substituted or unsubstituted heteroaryl. In embodiments, R³ issubstituted alkyl. In embodiments, R³ is substituted heteroalkyl. Inembodiments, R³ is substituted cycloalkyl. In embodiments, R³ issubstituted heterocycloalkyl. In embodiments, R³ is substituted aryl. Inembodiments, R³ is substituted heteroaryl. In embodiments, R³ isunsubstituted alkyl. In embodiments, R³ is unsubstituted heteroalkyl. Inembodiments, R³ is unsubstituted cycloalkyl. In embodiments, R³ isunsubstituted heterocycloalkyl. In embodiments, R³ is unsubstitutedaryl. In embodiments, R³ is unsubstituted heteroaryl.

In embodiments, R³ is independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R³ is independently halogen, —CF₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl,or substituted or unsubstituted 2 to 5 membered heteroalkyl.

In embodiments, R³ is independently halogen. In embodiments, R³ isindependently —CF₃. In embodiments, R³ is independently —CN. Inembodiments, R³ is independently —OH. In embodiments, R³ isindependently —NH₂. In embodiments, R³ is independently —COOH. Inembodiments, R³ is independently —CONH₂. In embodiments, R³ isindependently —NO₂. In embodiments, R³ is independently —SH. Inembodiments, R³ is independently —SO₃H. In embodiments, R³ isindependently —SO₄H. In embodiments, R³ is independently —SO₂NH₂. Inembodiments, R³ is independently —NHNH₂. In embodiments, R³ isindependently —ONH₂. In embodiments, R³ is independently —NHC═(O)NHNH₂.In embodiments, R³ is independently —NHC═(O)NH₂. In embodiments, R³ isindependently —NHSO₂H. In embodiments, R³ is independently —NHC═(O)H. Inembodiments, R³ is independently —NHC(O)OH. In embodiments, R³ isindependently —NHOH. In embodiments, R³ is independently —CHF₂. Inembodiments, R³ is independently —CH₂F. In embodiments, R³ isindependently —OCF₃. In embodiments, R³ is independently —OCHF₂. Inembodiments, R³ is independently substituted or unsubstituted (C₁-C₅)alkyl. In embodiments, R³ is independently substituted or unsubstituted2 to 5 membered heteroalkyl. In embodiments, R³ is independentlysubstituted (C₁-C₅) alkyl. In embodiments, R³ is independentlysubstituted 2 to 5 membered heteroalkyl. In embodiments, R³ isindependently unsubstituted (C₁-C₅) alkyl. In embodiments, R³ isindependently unsubstituted 2 to 5 membered heteroalkyl. In embodiments,R³ is independently substituted or unsubstituted butyl. In embodiments,R³ is independently substituted or unsubstituted butoxy. In embodiments,R³ is independently substituted butyl. In embodiments, R³ isindependently substituted butoxy. In embodiments, R³ is independentlyunsubstituted butyl. In embodiments, R³ is independently unsubstitutedbutoxy. In embodiments, R³ is independently substituted or unsubstitutedpropyl. In embodiments, R³ is independently substituted or unsubstitutedpropoxy. In embodiments, R³ is independently substituted propyl. Inembodiments, R³ is independently substituted propoxy. In embodiments, R³is independently unsubstituted propyl. In embodiments, R³ isindependently unsubstituted propoxy. In embodiments, R³ is independentlysubstituted or unsubstituted ethyl. In embodiments, R³ is independentlysubstituted or unsubstituted ethoxy. In embodiments, R³ is independentlysubstituted ethyl. In embodiments, R³ is independently substitutedethoxy. In embodiments, R³ is independently unsubstituted ethyl. Inembodiments, R³ is independently unsubstituted ethoxy. In embodiments,R³ is independently substituted or unsubstituted methyl. In embodiments,R³ is independently substituted or unsubstituted methoxy. Inembodiments, R³ is independently substituted methyl. In embodiments, R³is independently substituted methoxy. In embodiments, R³ isindependently unsubstituted methyl. In embodiments, R³ is independentlyunsubstituted methoxy. In embodiments, R³ is independently hydrogen.

In embodiments, R^(3D) and R^(3B) may optionally be joined to form asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R^(3B) and R^(3A) mayoptionally be joined to form a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R^(3A) and R^(3C) may optionally be joined to form asubstituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R^(3C) and R^(3E) mayoptionally be joined to form a substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

R^(3A) is independently hydrogen, halogen, —CX₃, —CN, —SO_(n)R¹⁰,—SO_(v)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸, —NHC═(O)NR⁷R⁸,—N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰,—NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂, —CH₂X, —OCX₃, —OCHX₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R^(3A) ishydrogen,

halogen, —CX^(3A) ₃, —CHX^(3A) ₂, —OCH₂X^(3A), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3A) ₃, —OCHX^(3A) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R^(3A) is independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3A) is independently halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.

In embodiments, R^(3A) is independently halogen. In embodiments, R^(3A)is independently —CF₃. In embodiments, R^(3A) is independently —CN. Inembodiments, R^(3A) is independently —OH. In embodiments, R^(3A) isindependently —NH₂. In embodiments, R^(3A) is independently —COOH. Inembodiments, R^(3A) is independently —CONH₂. In embodiments, R^(3A) isindependently —NO₂. In embodiments, R^(3A) is independently —SH. Inembodiments, R^(3A) is independently —SO₃H. In embodiments, R^(3A) isindependently —SO₄H. In embodiments, R^(3A) is independently —SO₂NH₂. Inembodiments, R^(3A) is independently —NHNH₂. In embodiments, R^(3A) isindependently —ONH₂. In embodiments, R^(3A) is independently—NHC═(O)NHNH₂. In embodiments, R^(3A) is independently —NHC═(O)NH₂. Inembodiments, R^(3A) is independently —NHSO₂H. In embodiments, R^(3A) isindependently —NHC═(O)H. In embodiments, R^(3A) is independently—NHC(O)OH. In embodiments, R^(3A) is independently —NHOH. Inembodiments, R^(3A) is independently —CHF₂. In embodiments, R^(3A) isindependently —CH₂F. In embodiments, R^(3A) is independently —OCF₃. Inembodiments, R^(3A) is independently —OCH_(F2).

In embodiments, R^(3A) is independently substituted or unsubstituted(C₁-C₅) alkyl. In embodiments, R^(3A) is independently substituted orunsubstituted 2 to 5 membered heteroalkyl. In embodiments, R^(3A) isindependently substituted (C₁-C₅) alkyl. In embodiments, R^(3A) isindependently substituted 2 to 5 membered heteroalkyl. In embodiments,R^(3A) is independently unsubstituted (C₁-C₅) alkyl. In embodiments,R^(3A) is independently unsubstituted 2 to 5 membered heteroalkyl. Inembodiments, R^(3A) is independently substituted or unsubstituted butyl.In embodiments, R^(3A) is independently substituted or unsubstitutedbutoxy. In embodiments, R^(3A) is independently substituted butyl. Inembodiments, R^(3A) is independently substituted butoxy. In embodiments,R^(3A) is independently unsubstituted butyl. In embodiments, R^(3A) isindependently unsubstituted butoxy. In embodiments, R^(3A) isindependently substituted or unsubstituted propyl. In embodiments,R^(3A) is independently substituted or unsubstituted propoxy. Inembodiments, R^(3A) is independently substituted propyl. In embodiments,R^(3A) is independently substituted propoxy. In embodiments, R^(3A) isindependently unsubstituted propyl. In embodiments, R^(3A) isindependently unsubstituted propoxy. In embodiments, R^(3A) isindependently substituted or unsubstituted ethyl. In embodiments, R^(3A)is independently substituted or unsubstituted ethoxy. In embodiments,R^(3A) is independently substituted ethyl. In embodiments, R^(3A) isindependently substituted ethoxy. In embodiments, R^(3A) isindependently unsubstituted ethyl. In embodiments, R^(3A) isindependently unsubstituted ethoxy. In embodiments, R^(3A) isindependently substituted or unsubstituted methyl. In embodiments,R^(3A) is independently substituted or unsubstituted methoxy. Inembodiments, R^(3A) is independently substituted methyl. In embodiments,R^(3A) is independently substituted methoxy. In embodiments, R^(3A) isindependently unsubstituted methyl. In embodiments, R^(3A) isindependently unsubstituted methoxy. In embodiments, R^(3A) isindependently hydrogen.

In embodiments, R^(3A) is independently hydrogen,

halogen, —CX^(3A) ₃, —CHX^(3A) ₂, —OCH₂X^(3A), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3A) ₃, —OCHX^(3A) ₂, R^(36A)-substituted or unsubstituted alkyl,R^(36A)-substituted or unsubstituted heteroalkyl, R^(36A)-substituted orunsubstituted cycloalkyl, R^(36A)-substituted or unsubstitutedheterocycloalkyl, R^(36A)-substituted or unsubstituted aryl, orR^(36A)-substituted or unsubstituted heteroaryl. X^(3A) is independentlyhalogen. In embodiments, X^(3A) is independently F or Cl.

R^(36A) is independently oxo,

halogen, —CX^(36A) ₃, —CHX^(36A) ₂, —OCH₂X^(36A), —OCHX^(36A) ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX³⁶ ₃, —OCHX³⁶ ₂, R^(37A)-substituted orunsubstituted alkyl, R^(37A)-substituted or unsubstituted heteroalkyl,R^(37A)-substituted or unsubstituted cycloalkyl, R^(37A)-substituted orunsubstituted heterocycloalkyl, R^(37A)-substituted or unsubstitutedaryl, or R^(37A)-substituted or unsubstituted heteroaryl. X^(36A) isindependently halogen. In embodiments, X^(36A) is independently F or Cl.

R^(37A) is independently oxo,

halogen, —CX^(37A) ₃, —CHX^(37A) ₂, —OCH₂X^(37A), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(37A) ₃, —OCHX^(37A) ₂, R^(38A)-substituted or unsubstituted alkyl,R^(38A)-substituted or unsubstituted heteroalkyl, R^(38A)-substituted orunsubstituted cycloalkyl, R^(38A)-substituted or unsubstitutedheterocycloalkyl, R^(38A)-substituted or unsubstituted aryl, orR^(38A)-substituted or unsubstituted heteroaryl. X^(37A) isindependently halogen. In embodiments, X^(37A) is independently F or Cl.

R^(3B) is independently hydrogen, halogen, —CX₃, —CN, —SO_(n)R¹⁰,—SO_(v)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸, —NHC═(O)NR⁷R⁸,—N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰,—NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂, —CH₂X, —OCX₃, —OCHX₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R^(3B) ishydrogen, oxo,

halogen, —CX^(3B) ₃, —CHX^(3B) ₂, —OCH₂X^(3B) ₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3B) ₃, —OCHX^(3B) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R^(3B) is independently hydrogen,

halogen, —CX^(3B) ₃, —CHX^(3B) ₂, —OCH₂X^(3B), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3B) ₃, —OCHX^(3B) ₂, R^(36B)-substituted or unsubstituted alkyl,R^(36B)-substituted or unsubstituted heteroalkyl, R^(36B)-substituted orunsubstituted cycloalkyl, alkyl, R^(36B)-substituted or unsubstitutedheterocycloalkyl, R^(36B)-substituted or unsubstituted aryl, orR^(36B)-substituted or unsubstituted heteroaryl. X^(3B) is independentlyhalogen. In embodiments, X^(3B) is independently F or Cl.

R^(36B) is independently oxo,

halogen, —CX^(36B) ₃, —CHX^(36B) ₂, —OCH₂X^(36B), —OCHX^(36B) ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX^(36B) ₃, —OCHX^(36B) ₂, R^(37B)-substituted orunsubstituted alkyl, R^(37B)-substituted or unsubstituted heteroalkyl,R^(37B)-substituted or unsubstituted cycloalkyl, R^(37B)-substituted orunsubstituted heterocycloalkyl, R^(37B)-substituted or unsubstitutedaryl, or R^(37B)-substituted or unsubstituted heteroaryl. X^(36B) isindependently halogen. In embodiments, X^(36B) is independently F or Cl.

R^(37B) is independently oxo,

halogen, —CX^(37B) ₃, —CHX^(37B) ₂, —OCH₂X^(37B), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(37B) ₃, —OCHX^(37B) ₂, R^(38B)-substituted or unsubstituted alkyl,R^(38B)-substituted or unsubstituted heteroalkyl, R^(38B)-substituted orunsubstituted cycloalkyl, R^(38B)-substituted or unsubstitutedheterocycloalkyl, R^(38B)-substituted or unsubstituted aryl, orR^(38B)-substituted or unsubstituted heteroaryl. X^(37B) isindependently halogen. In embodiments, X^(37B) is independently F or Cl.

In embodiments, R^(3B) is independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3B) is independently halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3B) is independently halogen.In embodiments, R^(3B) is independently —CF₃. In embodiments, R^(3B) isindependently —CN. In embodiments, R^(3B) is independently —OH. Inembodiments, R^(3B) is independently —NH₂. In embodiments, R^(3B) isindependently —COOH. In embodiments, R^(3B) is independently —CONH₂. Inembodiments, R^(3B) is independently —NO₂. In embodiments, R^(3B) isindependently —SH. In embodiments, R^(3B) is independently —SO₃H. Inembodiments, R^(3B) is independently —SO_(4H). In embodiments, R^(3B) isindependently —SO₂NH₂. In embodiments, R^(3B) is independently —NHNH₂.In embodiments, R^(3B) is independently —ONH₂. In embodiments, R^(3B) isindependently —NHC═(O)NHNH₂. In embodiments, R^(3B) is independently—NHC═(O)NH₂. In embodiments, R^(3B) is independently —NHSO₂H. Inembodiments, R^(3B) is independently —NHC═(O)H. In embodiments, R^(3B)is independently —NHC(O)OH. In embodiments, R^(3B) is independently—NHOH. In embodiments, R^(3B) is independently —CHF₂. In embodiments,R^(3B) is independently —CH₂F. In embodiments, R^(3B) is independently—OCF₃. In embodiments, R^(3B) is independently —OCHF₂. In embodiments,R^(3B) is independently substituted or unsubstituted (C₁-C₅) alkyl. Inembodiments, R^(3B) is independently substituted or unsubstituted 2 to 5membered heteroalkyl.

In embodiments, R^(3B) is independently substituted (C₁-C₅) alkyl. Inembodiments, R^(3B) is independently substituted 2 to 5 memberedheteroalkyl. In embodiments, R^(3B) is independently unsubstituted(C₁-C₅) alkyl. In embodiments, R^(3B) is independently unsubstituted 2to 5 membered heteroalkyl. In embodiments, R^(3B) is independentlysubstituted or unsubstituted butyl. In embodiments, R^(3B) isindependently substituted or unsubstituted butoxy. In embodiments,R^(3B) is independently substituted butyl. In embodiments, R^(3B) isindependently substituted butoxy. In embodiments, R^(3B) isindependently unsubstituted butyl. In embodiments, R^(3B) isindependently unsubstituted butoxy. In embodiments, R^(3B) isindependently substituted or unsubstituted propyl. In embodiments,R^(3B) is independently substituted or unsubstituted propoxy. Inembodiments, R^(3B) is independently substituted propyl. In embodiments,R^(3B) is independently substituted propoxy. In embodiments, R^(3B) isindependently unsubstituted propyl. In embodiments, R^(3B) isindependently unsubstituted propoxy. In embodiments, R^(3B) isindependently substituted or unsubstituted ethyl. In embodiments, R^(3B)is independently substituted or unsubstituted ethoxy. In embodiments,R^(3B) is independently substituted ethyl. In embodiments, R^(3B) isindependently substituted ethoxy. In embodiments, R^(3B) isindependently unsubstituted ethyl. In embodiments, R^(3B) isindependently unsubstituted ethoxy. In embodiments, R^(3B) isindependently substituted or unsubstituted methyl. In embodiments,R^(3B) is independently substituted or unsubstituted methoxy. Inembodiments, R^(3B) is independently substituted methyl. In embodiments,R^(3B) is independently substituted methoxy. In embodiments, R^(3B) isindependently unsubstituted methyl. In embodiments, R^(3B) isindependently unsubstituted methoxy. In embodiments, R^(3B) isindependently hydrogen.

R^(3C) is independently hydrogen, halogen, —CX₃, —CN, —SO_(n)R¹⁰,—SO_(v)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸, —NHC═(O)NR⁷R⁸,—N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R,—NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂, —CH₂X, —OCX₃, —OCHX₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R^(3C) ishydrogen, oxo,

halogen, —CX^(3C) ₃, —CHX^(3C) ₂, —OCH₂X^(3C), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3C) ₃, —OCHX^(3C) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R^(3C) is independently hydrogen,

halogen, —CX^(3C) ₃, —CHX^(3C) ₂, —OCH₂X^(3C), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3C) ₃, —OCHX^(3C) ₂, R^(36C)-substituted or unsubstituted alkyl,R^(36C)-substituted or unsubstituted heteroalkyl, R^(36C)-substituted orunsubstituted cycloalkyl, R^(36C)-substituted or unsubstitutedheterocycloalkyl, R^(36C)-substituted or unsubstituted aryl, orR^(36C)-substituted or unsubstituted heteroaryl. X^(3C) is independentlyhalogen. In embodiments, X^(3C) is independently F or Cl.

R^(36C) is independently oxo,

halogen, —CX^(36C) ₃, —CHX^(36C) ₂, —OCH₂X^(36C), —OCHX^(36C) ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX^(36C) ₃, —OCHX^(36C) ₂, R^(37C) substituted orunsubstituted alkyl, R^(37C)-substituted or unsubstituted heteroalkyl,R^(37C)-substituted or unsubstituted cycloalkyl, R^(37C)-substituted orunsubstituted heterocycloalkyl, R^(37C)-substituted or unsubstitutedaryl, or R^(37C)-substituted or unsubstituted heteroaryl. X^(36C) isindependently halogen. In embodiments, X^(36C) is independently F or Cl.

R^(37C) is independently oxo,

halogen, —CX^(37C) ₃, —CHX^(37C) ₂, —OCH₂X^(37C), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(37C) ₃, —OCHX^(37C) ₂, R^(38C)-substituted or unsubstituted alkyl,R^(38C)-substituted or unsubstituted heteroalkyl, R^(38C)-substituted orunsubstituted cycloalkyl, R^(38C)-substituted or unsubstitutedheterocycloalkyl, R^(38C)-substituted or unsubstituted aryl, orR^(38C)-substituted or unsubstituted heteroaryl. X^(37C) isindependently halogen. In embodiments, X^(37C) is independently F or Cl.

In embodiments, R^(3C) is independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3C) is independently halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3C) is independently halogen.In embodiments, R^(3C) is independently —CF₃. In embodiments, R^(3C) isindependently —CN. In embodiments, R^(3C) is independently —OH. Inembodiments, R^(3C) is independently —NH₂. In embodiments, R^(3C) isindependently —COOH. In embodiments, R^(3C) is independently —CONH₂. Inembodiments, R^(3C) is independently —NO₂. In embodiments, R^(3C) isindependently —SH. In embodiments, R^(3C) is independently —SO₃H. Inembodiments, R^(3C) is independently —SO_(4H). In embodiments, R^(3C) isindependently —SO₂NH₂. In embodiments, R^(3C) is independently —NHNH₂.In embodiments, R^(3C) is independently —ONH₂. In embodiments, R^(3C) isindependently —NHC═(O)NHNH₂. In embodiments, R^(3C) is independently—NHC═(O)NH₂. In embodiments, R^(3C) is independently —NHSO₂H. Inembodiments, R^(3C) is independently —NHC═(O)H. In embodiments, R^(3C)is independently —NHC(O)OH. In embodiments, R^(3C) is independently—NHOH. In embodiments, R^(3C) is independently —CHF₂. In embodiments,R^(3C) is independently —CH₂F. In embodiments, R^(3C) is independently—OCF₃. In embodiments, R^(3C) is independently —OCHF₂.

In embodiments, R^(3C) is independently substituted or unsubstituted(C₁-C₅) alkyl. In embodiments, R^(3C) is independently substituted orunsubstituted 2 to 5 membered heteroalkyl. In embodiments, R^(3C) isindependently substituted (C₁-C₅) alkyl. In embodiments, R^(3C) isindependently substituted 2 to 5 membered heteroalkyl. In embodiments,R^(3C) is independently unsubstituted (C₁-C₅) alkyl. In embodiments,R^(3C) is independently unsubstituted 2 to 5 membered heteroalkyl. Inembodiments, R^(3C) is independently substituted or unsubstituted butyl.In embodiments, R^(3C) is independently substituted or unsubstitutedbutoxy. In embodiments, R^(3C) is independently substituted butyl. Inembodiments, R^(3C) is independently substituted butoxy. In embodiments,R^(3C) is independently unsubstituted butyl. In embodiments, R^(3C) isindependently unsubstituted butoxy. In embodiments, R^(3C) isindependently substituted or unsubstituted propyl. In embodiments,R^(3C) is independently substituted or unsubstituted propoxy. Inembodiments, R^(3C) is independently substituted propyl. In embodiments,R^(3C) is independently substituted propoxy. In embodiments, R^(3C) isindependently unsubstituted propyl. In embodiments, R^(3C) isindependently unsubstituted propoxy. In embodiments, R^(3C) isindependently substituted or unsubstituted ethyl. In embodiments, R^(3C)is independently substituted or unsubstituted ethoxy. In embodiments,R^(3C) is independently substituted ethyl. In embodiments, R^(3C) isindependently substituted ethoxy. In embodiments, R^(3C) isindependently unsubstituted ethyl. In embodiments, R^(3C) isindependently unsubstituted ethoxy. In embodiments, R^(3C) isindependently substituted or unsubstituted methyl. In embodiments,R^(3C) is independently substituted or unsubstituted methoxy. Inembodiments, R^(3C) is independently substituted methyl. In embodiments,R^(3C) is independently substituted methoxy. In embodiments, R^(3C) isindependently unsubstituted methyl. In embodiments, R^(3C) isindependently unsubstituted methoxy. In embodiments, R^(3C) isindependently hydrogen.

R^(3D) is independently hydrogen, halogen, —CX₃, —CN, —SO_(n)R¹⁰,—SO_(v)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸, —NHC═(O)NR⁷R⁸,—N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰,—NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂, —CH₂X, —OCX₃, —OCHX₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R^(3D) ishydrogen, oxo,

halogen, —CX^(3D) ₃, —CHX^(3D) ₂, —OCH₂X^(3D), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3D) ₃, —OCHX^(3D) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R^(3D) is independently hydrogen,

halogen, —CX^(3D) ₃, —CHX^(3D) ₂, —OCH₂X^(3D), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3D) ₃, —OCHX^(3D) ₂, R^(36D)-substituted or unsubstituted alkyl,R^(36D)-substituted or unsubstituted heteroalkyl, R^(36D)-substituted orunsubstituted cycloalkyl, R^(36D)-substituted or unsubstitutedheterocycloalkyl, R^(36D)-substituted or unsubstituted aryl, orR^(36D)-substituted or unsubstituted heteroaryl. X^(3D) is independentlyhalogen. In embodiments, X^(3D) is independently F or Cl.

R^(36D) is independently oxo,

halogen, —CX^(36D) ₃, —CHX^(36D) ₂, —OCH₂X^(36D), —OCHX^(36D) ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX^(36D) ₃, —OCHX^(36D) ₂, R^(37D)-substituted orunsubstituted alkyl, R^(37D)-substituted or unsubstituted heteroalkyl,R^(37D)-substituted or unsubstituted cycloalkyl, R^(37D)-substituted orunsubstituted heterocycloalkyl, R^(37D)-substituted or unsubstitutedaryl, or R^(37D)-substituted or unsubstituted heteroaryl. X^(36D) isindependently halogen. In embodiments, X^(36D) is independently F or Cl.

R^(37D) is independently oxo,

halogen, —CX^(37D) ₃, —CHX^(37D) ₂, —OCH₂X^(37D), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(37D) ₃, —OCHX^(37D) ₂, R^(38D)-substituted or unsubstituted alkyl,R^(38D)-substituted or unsubstituted heteroalkyl, R^(38D)-substituted orunsubstituted cycloalkyl, R^(38D)-substituted or unsubstitutedheterocycloalkyl, R^(38D)-substituted or unsubstituted aryl, orR^(38D)-substituted or unsubstituted heteroaryl. X^(37D) isindependently halogen. In embodiments, X^(37D) is independently F or Cl.

In embodiments, R^(3D) is independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3D) is independently halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3D) is independently halogen.In embodiments, R^(3D) is independently —CF₃. In embodiments, R^(3D) isindependently —CN. In embodiments, R^(3D) is independently —OH. Inembodiments, R^(3D) is independently —NH₂. In embodiments, R^(3D) isindependently —COOH. In embodiments, R^(3D) is independently —CONH₂. Inembodiments, R^(3D) is independently —NO₂. In embodiments, R^(3D) isindependently —SH. In embodiments, R^(3D) is independently —SO₃H. Inembodiments, R^(3D) is independently —SO_(4H). In embodiments, R^(3D) isindependently —SO₂NH₂. In embodiments, R^(3D) is independently —NHNH₂.In embodiments, R^(3D) is independently —ONH₂. In embodiments, R^(3D) isindependently —NHC═(O)NHNH₂. In embodiments, R^(3D) is independently—NHC═(O)NH₂. In embodiments, R^(3D) is independently —NHSO₂H. Inembodiments, R^(3D) is independently —NHC═(O)H. In embodiments, R^(3D)is independently —NHC(O)OH. In embodiments, R^(3D) is independently—NHOH. In embodiments, R^(3D) is independently —CHF₂. In embodiments,R^(3D) is independently —CH₂F. In embodiments, R^(3D) is independently—OCF₃. In embodiments, R^(3D) is independently —OCHF₂.

In embodiments, R^(3D) is independently substituted or unsubstituted(C₁-C₅) alkyl. In embodiments, R^(3D) is independently substituted orunsubstituted 2 to 5 membered heteroalkyl. In embodiments, R^(3D) isindependently substituted (C₁-C₅) alkyl. In embodiments, R^(3D) isindependently substituted 2 to 5 membered heteroalkyl. In embodiments,R^(3D) is independently unsubstituted (C₁-C₅) alkyl. In embodiments,R^(3D) is independently unsubstituted 2 to 5 membered heteroalkyl. Inembodiments, R^(3D) is independently substituted or unsubstituted butyl.In embodiments, R^(3D) is independently substituted or unsubstitutedbutoxy. In embodiments, R^(3D) is independently substituted butyl. Inembodiments, R^(3D) is independently substituted butoxy. In embodiments,R^(3D) is independently unsubstituted butyl. In embodiments, R^(3D) isindependently unsubstituted butoxy. In embodiments, R^(3D) isindependently substituted or unsubstituted propyl. In embodiments,R^(3D) is independently substituted or unsubstituted propoxy. Inembodiments, R^(3D) is independently substituted propyl. In embodiments,R^(3D) is independently substituted propoxy. In embodiments, R^(3D) isindependently unsubstituted propyl. In embodiments, R^(3D) isindependently unsubstituted propoxy. In embodiments, R^(3D) isindependently substituted or unsubstituted ethyl. In embodiments, R^(3D)is independently substituted or unsubstituted ethoxy. In embodiments,R^(3D) is independently substituted ethyl. In embodiments, R^(3D) isindependently substituted ethoxy. In embodiments, R^(3D) isindependently unsubstituted ethyl. In embodiments, R^(3D) isindependently unsubstituted ethoxy. In embodiments, R^(3D) isindependently substituted or unsubstituted methyl. In embodiments,R^(3D) is independently substituted or unsubstituted methoxy. Inembodiments, R^(3D) is independently substituted methyl. In embodiments,R^(3D) is independently substituted methoxy. In embodiments, R^(3D) isindependently unsubstituted methyl. In embodiments, R^(3D) isindependently unsubstituted methoxy. In embodiments, R^(3D) isindependently hydrogen.

R^(3E) is independently hydrogen, halogen, —CX₃, —CN, —SO_(n)R¹⁰,—SO_(v)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸, —NHC═(O)NR⁷R⁸,—N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰,—NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂, —CH₂X, —OCX₃, —OCHX₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In embodiments, R^(3E) ishydrogen, oxo,

halogen, —CX^(3E) ₃, —CHX^(3E) ₂, —OCH₂X^(3E), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3E) ₃, —OCHX^(3E) ₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R^(3E) is independently hydrogen,

halogen, —CX^(3E) ₃, —CHX^(3E) ₂, —OCH₂X^(3E), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(3E) ₃, —OCHX^(3E) ₂, R^(36E)-substituted or unsubstituted alkyl,R^(36E)-substituted or unsubstituted heteroalkyl, R^(36E)-substituted orunsubstituted cycloalkyl, R^(36E)-substituted or unsubstitutedheterocycloalkyl, R^(36E)-substituted or unsubstituted aryl, orR^(36E)-substituted or unsubstituted heteroaryl. X^(3E) is independentlyhalogen. In embodiments, X^(3E) is independently F or Cl.

R^(36E) is independently oxo,

halogen, —CX^(36E) ₃, —CHX^(36E) ₂, —OCH₂X^(36E), —OCHX^(36E) ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —OCX^(36E) ₃, —OCHX^(36E) ₂, R^(37E)-substituted orunsubstituted alkyl, R^(37E)-substituted or unsubstituted heteroalkyl,R^(37E)-substituted or unsubstituted cycloalkyl, R^(37E)-substituted orunsubstituted heterocycloalkyl, R^(37E)-substituted or unsubstitutedaryl, or R^(37E)-substituted or unsubstituted heteroaryl. X^(36E) isindependently halogen. In embodiments, X^(36E) is independently F or Cl.

R^(37E) is independently oxo,

halogen, —CX^(37E) ₃, —CHX^(37E) ₂, —OCH₂X^(37E), —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX^(37E) ₃, —OCHX^(37E) ₂, R^(38E)-substituted or unsubstituted alkyl,R^(38E)-substituted or unsubstituted heteroalkyl, R^(38E)-substituted orunsubstituted cycloalkyl, R^(38E)-substituted or unsubstitutedheterocycloalkyl, R^(38E)-substituted or unsubstituted aryl, orR^(38E)-substituted or unsubstituted heteroaryl. X^(37E) isindependently halogen. In embodiments, X^(37E) is independently F or Cl.

In embodiments, R^(3E) is independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3E) is independently halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3E) is independently halogen.In embodiments, R^(3E) is independently —CF₃. In embodiments, R^(3E) isindependently —CN. In embodiments, R^(3E) is independently —OH. Inembodiments, R^(3E) is independently —NH₂. In embodiments, R^(3E) isindependently —COOH. In embodiments, R^(3E) is independently —CONH₂. Inembodiments, R^(3E) is independently —NO₂. In embodiments, R^(3E) isindependently —SH. In embodiments, R^(3E) is independently —SO₃H. Inembodiments, R^(3E) is independently —SO_(4H). In embodiments, R^(3E) isindependently —SO₂NH₂. In embodiments, R^(3E) is independently —NHNH₂.In embodiments, R^(3E) is independently —ONH₂. In embodiments, R^(3E) isindependently —NHC═(O)NHNH₂. In embodiments, R^(3E) is independently—NHC═(O)NH₂. In embodiments, R^(3E) is independently —NHSO₂H. Inembodiments, R^(3E) is independently —NHC═(O)H. In embodiments, R^(3E)is independently —NHC(O)OH. In embodiments, R^(3E) is independently—NHOH. In embodiments, R^(3E) is independently —CHF₂. In embodiments,R^(3E) is independently —CH₂F. In embodiments, R^(3E) is independently—OCF₃. In embodiments, R^(3E) is independently —OCHF₂.

In embodiments, R^(3E) is independently substituted or unsubstituted(C₁-C₅) alkyl. In embodiments, R^(3E) is independently substituted orunsubstituted 2 to 5 membered heteroalkyl. In embodiments, R^(3E) isindependently substituted (C₁-C₅) alkyl. In embodiments, R^(3E) isindependently substituted 2 to 5 membered heteroalkyl. In embodiments,R^(3E) is independently unsubstituted (C₁-C₅) alkyl. In embodiments,R^(3E) is independently unsubstituted 2 to 5 membered heteroalkyl. Inembodiments, R^(3E) is independently substituted or unsubstituted butyl.In embodiments, R^(3E) is independently substituted or unsubstitutedbutoxy. In embodiments, R^(3E) is independently substituted butyl. Inembodiments, R^(3E) is independently substituted butoxy. In embodiments,R^(3E) is independently unsubstituted butyl. In embodiments, R^(3E) isindependently unsubstituted butoxy. In embodiments, R^(3E) isindependently substituted or unsubstituted propyl. In embodiments,R^(3E) is independently substituted or unsubstituted propoxy. Inembodiments, R^(3E) is independently substituted propyl. In embodiments,R^(3E) is independently substituted propoxy. In embodiments, R^(3E) isindependently unsubstituted propyl. In embodiments, R^(3E) isindependently unsubstituted propoxy. In embodiments, R^(3E) isindependently substituted or unsubstituted ethyl. In embodiments, R^(3E)is independently substituted or unsubstituted ethoxy. In embodiments,R^(3E) is independently substituted ethyl. In embodiments, R^(3E) isindependently substituted ethoxy. In embodiments, R^(3E) isindependently unsubstituted ethyl. In embodiments, R^(3E) isindependently unsubstituted ethoxy. In embodiments, R^(3E) isindependently substituted or unsubstituted methyl. In embodiments,R^(3E) is independently substituted or unsubstituted methoxy. Inembodiments, R^(3E) is independently substituted methyl. In embodiments,R^(3E) is independently substituted methoxy. In embodiments, R^(3E) isindependently unsubstituted methyl. In embodiments, R^(3E) isindependently unsubstituted methoxy. In embodiments, R^(3E) isindependently hydrogen.

In embodiments, two adjacent R³ substituents (e.g., R^(3B) and R^(3D),R^(3B) and R^(3A), R^(3A) and R^(3C), R^(3C) and R^(3E)) may optionallybe joined to form a substituted or unsubstituted (C₃-C₁₀) cycloalkyl orsubstituted or unsubstituted 3 to 10 membered heterocycloalkyl,substituted or unsubstituted (C₆-C₁₀) aryl, or substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacentR³ substituents may optionally be joined to form a substituted orunsubstituted (C₃-C₁₀) cycloalkyl. In embodiments, two adjacent R³substituents may optionally be joined to form substituted orunsubstituted 3 to 10 membered heterocycloalkyl. In embodiments, twoadjacent R³ substituents may optionally be joined to form substituted orunsubstituted (C₆-C₁₀) aryl. In embodiments, two adjacent R³substituents may optionally be joined to form substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacentR³ substituents may optionally be joined to form2,2-dimethyl-1,3-dioxanyl. In embodiments, two adjacent R³ substituentsmay optionally be joined to form 1,3-dioxanyl. In embodiments, twoadjacent R³ substituents may optionally be joined to form1,3-dioxolanyl. In embodiments, two adjacent R³ substituents mayoptionally be joined to form 2,2-dimethyl-1,3-dioxolanyl.

Each R⁷, R⁸, R⁹, and R¹⁰ is independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷ and R⁸ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl.

Each R⁷ and R⁸ substituents bonded to the same nitrogen atom may bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl. Each R⁷ and R⁸ substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheterocycloalkyl or unsubstituted heteroaryl. Each R⁷ and R⁸substituents bonded to the same nitrogen atom may be joined to form asubstituted or unsubstituted 4 to 6 membered heterocycloalkyl or 5 to 6membered heteroaryl. Each R⁷ and R⁸ substituents bonded to the samenitrogen atom may be joined to form an unsubstituted 4 to 6 memberedheterocycloalkyl or unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁷ is independently hydrogen, oxo,

halogen, —CX⁷ ₃, —CHX⁷ ₂, —OCH₂X⁷, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁷ ₃, —OCHX⁷ ₂,R⁴⁸-substituted or unsubstituted alkyl, R⁴⁸-substituted or unsubstitutedheteroalkyl, R⁴⁸-substituted or unsubstituted cycloalkyl, R⁴⁸substituted or unsubstituted heterocycloalkyl, R⁴⁸-substituted orunsubstituted aryl, or R⁴⁸-substituted or unsubstituted heteroaryl. X⁷is independently halogen. In embodiments, X⁷ is independently F or Cl.

R⁴⁸ is independently oxo,

halogen, —CX⁴⁸ ₃, —CHX⁴⁸ ₂, —OCH₂X⁴⁸, —OCHX⁴⁸ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁴⁸ ₃, —OCHX⁴⁸ ₂, R⁴⁹-substituted or unsubstituted alkyl,R⁴⁹-substituted or unsubstituted heteroalkyl, R⁴⁹-substituted orunsubstituted cycloalkyl, R⁴⁹-substituted or unsubstitutedheterocycloalkyl, R⁴⁹-substituted or unsubstituted aryl, orR⁴⁹-substituted or unsubstituted heteroaryl. X⁴⁸ is independentlyhalogen. In embodiments, X⁴⁸ is independently F or Cl.

R⁴⁹ is independently oxo,

halogen, —CX⁴⁹ ₃, —CHX⁴⁹ ₂, —OCH₂X⁴⁹, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴⁹ ₃, —OCHX⁴⁹ ₂,R⁵⁰-substituted or unsubstituted alkyl, R⁵⁰-substituted or unsubstitutedheteroalkyl, R⁵⁰-substituted or unsubstituted cycloalkyl,R⁵⁰-substituted or unsubstituted heterocycloalkyl, R⁵⁰-substituted orunsubstituted aryl, or R⁵⁰-substituted or unsubstituted heteroaryl. X⁴⁹is independently halogen. In embodiments, X⁴⁹ is independently F or Cl.

In embodiments, R⁸ is independently hydrogen, oxo,

halogen, —CX⁸ ₃, —CHX₂, —OCH₂X⁸, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁸ ₃, —OCHX⁸ ₂,R⁵¹-substituted or unsubstituted alkyl, R⁵¹-substituted or unsubstitutedheteroalkyl, R⁵¹-substituted or unsubstituted cycloalkyl, R⁵¹substituted or unsubstituted heterocycloalkyl, R⁵¹-substituted orunsubstituted aryl, or R⁵¹-substituted or unsubstituted heteroaryl. X⁸is independently halogen. In embodiments, X⁸ is independently F or Cl.

R⁵¹ is independently oxo,

halogen, —CX⁵¹ ₃, —CHX⁵¹ ₂, —OCH₂X⁵¹, —OCHX⁵¹ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁵¹ ₃, —OCHX⁵¹ ₂, R⁵²-substituted or unsubstituted alkyl,R⁵²-substituted or unsubstituted heteroalkyl, R⁵²-substituted orunsubstituted cycloalkyl, R⁵²-substituted or unsubstitutedheterocycloalkyl, R⁵²-substituted or unsubstituted aryl, orR⁵²-substituted or unsubstituted heteroaryl. X⁵¹ is independentlyhalogen. In embodiments, X⁵¹ is independently F or Cl.

R⁵² is independently oxo,

halogen, —CX⁵² ₃, —CHX⁵² ₂, —OCH₂X⁵², —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵² ₃, —OCHX⁵² ₂,R⁵³-substituted or unsubstituted alkyl, R⁵³-substituted or unsubstitutedheteroalkyl, R⁵³-substituted or unsubstituted cycloalkyl,R⁵³-substituted or unsubstituted heterocycloalkyl, R⁵³-substituted orunsubstituted aryl, or R⁵³-substituted or unsubstituted heteroaryl. X⁵²is independently halogen. In embodiments, X⁵² is independently F or Cl.

In embodiments, R⁹ is independently hydrogen, oxo,

halogen, —CX⁹ ₃, —CHX⁹ ₂, —OCH₂X⁹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹ ₃, —OCHX⁹²,R⁵⁴-substituted or unsubstituted alkyl, R⁵⁴-substituted or unsubstitutedheteroalkyl, R⁵⁴-substituted or unsubstituted cycloalkyl,R⁵⁴-substituted or unsubstituted heterocycloalkyl, R⁵⁴-substituted orunsubstituted aryl, or R⁵⁴-substituted or unsubstituted heteroaryl. X⁹is independently halogen. In embodiments, X⁹ is independently F or Cl.

R⁵⁴ is independently oxo,

halogen, —CX⁵⁴ ₃, —CHX⁵⁴ ₂, —OCH₂X⁵⁴, —OCHX⁵⁴ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁵⁴ ₃, —OCHX⁵⁴ ₂, R⁵⁵-substituted or unsubstituted alkyl,R⁵⁵-substituted or unsubstituted heteroalkyl, R⁵⁵-substituted orunsubstituted cycloalkyl, R⁵⁵-substituted or unsubstitutedheterocycloalkyl, R⁵⁵-substituted or unsubstituted aryl, orR⁵⁵-substituted or unsubstituted heteroaryl. X⁵⁴ is independentlyhalogen. In embodiments, X⁵⁴ is independently F or Cl.

R⁵⁵ is independently oxo,

halogen, —CX⁵⁵ ₃, —CHX⁵⁵ ₂, —OCH₂X⁵⁵, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵⁵ ₃, —OCHX⁵⁵ ₂,R⁵⁶-substituted or unsubstituted alkyl, R⁵⁶-substituted or unsubstitutedheteroalkyl, R⁵⁶-substituted or unsubstituted cycloalkyl, R⁵⁶substituted or unsubstituted heterocycloalkyl, R⁵⁶-substituted orunsubstituted aryl, or R⁵⁶-substituted or unsubstituted heteroaryl. X⁵⁵is independently halogen. In embodiments, X⁵⁵ is independently F or Cl.

In embodiments, R¹⁰ is independently hydrogen, oxo,

halogen, —CX¹⁰ ₃, —CHX¹⁰ ₂, —OCH₂X¹⁰, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹⁰ ₃, —OCHX¹⁰ ₂,R⁵⁷-substituted or unsubstituted alkyl, R⁵⁷-substituted or unsubstitutedheteroalkyl, R⁵⁷-substituted or unsubstituted cycloalkyl,R⁵⁷-substituted or unsubstituted heterocycloalkyl, R⁵⁷-substituted orunsubstituted aryl, or R⁵⁷-substituted or unsubstituted heteroaryl. X¹⁰is independently halogen. In embodiments, X¹⁰ is independently F or Cl.

R⁵⁷ is independently oxo,

halogen, —CX⁵⁷ ₃, —CHX⁵⁷ ₂, —OCH₂X⁵⁷, —OCHX⁵⁷ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁵⁷ ₃, —OCHX⁵⁷ ₂, R⁵⁸-substituted or unsubstituted alkyl,R⁵⁸-substituted or unsubstituted heteroalkyl, R⁵⁸-substituted orunsubstituted cycloalkyl, R⁵⁸-substituted or unsubstitutedheterocycloalkyl, R⁵⁸-substituted or unsubstituted aryl, orR⁵⁸-substituted or unsubstituted heteroaryl. X⁵⁷ is independentlyhalogen. In embodiments, X⁵⁷ is independently F or Cl.

R⁵⁸ is independently oxo,

halogen, —CX⁵⁸ ₃, —CHX⁵⁸ ₂, —OCH₂X⁵⁸, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁵⁸ ₃, —OCHX⁵⁸ ₂,R⁵⁹-substituted or unsubstituted alkyl, R⁵⁹-substituted or unsubstitutedheteroalkyl, R⁵⁹-substituted or unsubstituted cycloalkyl,R⁵⁹-substituted or unsubstituted heterocycloalkyl, R⁵⁹-substituted orunsubstituted aryl, or R⁵⁹-substituted or unsubstituted heteroaryl. X⁵⁸is independently halogen. In embodiments, X⁵⁸ is independently F or Cl.

The symbols m and v are independently 1 or 2. The symbol n isindependently an integer from 0 to 4. X is independently —Cl, —Br, —I,or —F. In embodiments, X is —Cl. In embodiments, X is —Br. Inembodiments, X is —I. In embodiments, X is or —F. In embodiments, X^(a)is —Cl. In embodiments, X^(a) is —Br. In embodiments, X^(a) is —I. Inembodiments, X^(a) is or —F.

In embodiments, Ring B is substituted or unsubstituted cycloalkyl. Inembodiments, Ring B is substituted or unsubstituted heterocycloalkyl. Inembodiments, Ring B is substituted or unsubstituted aryl. Inembodiments, Ring B is substituted or unsubstituted heteroaryl. Inembodiments, Ring B is substituted or unsubstituted (C₃-C₁₀) cycloalkyl,substituted or unsubstituted 3 to 10 membered heterocycloalkyl,substituted or unsubstituted (C₆-C₁₀) aryl, or substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, Ring B issubstituted or unsubstituted (C₃-C₁₀) cycloalkyl. In embodiments, Ring Bis substituted or unsubstituted 3 to 10 membered heterocycloalkyl. Inembodiments, Ring B is substituted or unsubstituted (C₆-C₁₀) aryl. Inembodiments, Ring B is substituted or unsubstituted 5 to 10 memberedheteroaryl. In embodiments, Ring B is substituted or unsubstituted(C₃-C₆) cycloalkyl. In embodiments, Ring B is substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, Ring Bis substituted or unsubstituted phenyl. In embodiments, Ring B issubstituted or unsubstituted naphthyl. In embodiments, Ring B issubstituted or unsubstituted 5 to 9 membered heteroaryl. In embodiments,Ring B is substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, Ring B is an unsubstituted 5 to 6 membered heteroaryl. Inembodiments, Ring B is substituted or unsubstituted 5 memberedheteroaryl. In embodiments, Ring B is a substituted 5 memberedheteroaryl. In embodiments, Ring B is an unsubstituted 5 memberedheteroaryl.

In embodiments, Ring B is R⁴-substituted or unsubstituted (C₃-C₁₀)cycloalkyl, R⁴-substituted or unsubstituted 5 to 10 memberedheterocycloalkyl, R⁴-substituted or unsubstituted (C₆-C₁₀) aryl, orR⁴-substituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, Ring B is R⁴-substituted or unsubstituted (C₃-C₁₀)cycloalkyl or R⁴-substituted or unsubstituted 5 to 10 memberedheterocycloalkyl. In embodiments, Ring B is R⁴-substituted orunsubstituted (C₃-C₁₀) cycloalkyl. In embodiments, Ring B isR⁴-substituted or unsubstituted 3 to 10 membered heterocycloalkyl. Inembodiments, Ring B is R⁴-substituted or unsubstituted (C₆-C₁₀) aryl. Inembodiments, Ring B is R⁴-substituted or unsubstituted 5 to 10 memberedheteroaryl. In embodiments, Ring B is R⁴-substituted or unsubstituted(C₃-C₆) cycloalkyl. In embodiments, Ring B is R⁴-substituted orunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, Ring Bis R⁴-substituted or unsubstituted phenyl. In embodiments, Ring B isR⁴-substituted or unsubstituted naphthyl. In embodiments, Ring B isR⁴-substituted or unsubstituted 5 to 9 membered heteroaryl. Inembodiments, Ring B is R⁴-substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, Ring B is R⁴-substituted or unsubstitutedthienyl. In embodiments, Ring B is R⁴-substituted or unsubstitutedphenyl. In embodiments, Ring B is R⁴-substituted or unsubstitutedbenzothienyl. In embodiments, Ring B is R⁴-substituted or unsubstitutednaphthyl. In embodiments, Ring B is R⁴-substituted or unsubstitutedbenzofuranyl. In embodiments, Ring B is R⁴-substituted or unsubstitutedfuranyl. In embodiments, Ring B is R⁴-substituted or unsubstitutedpyrrolyl. In embodiments, Ring B is R⁴-substituted or unsubstituted2,3-dihydro-1H-indenyl.

In embodiments, Ring B is substituted cycloalkyl. In embodiments, Ring Bis substituted heterocycloalkyl. In embodiments, Ring B is substitutedaryl. In embodiments, Ring B is substituted heteroaryl. In embodiments,Ring B is substituted (C₃-C₁₀) cycloalkyl, substituted 3 to 10 memberedheterocycloalkyl, substituted (C₆-C₁₀) aryl, or substituted 5 to 10membered heteroaryl. In embodiments, Ring B is substituted (C₃-C₁₀)cycloalkyl. In embodiments, Ring B is substituted 3 to 10 memberedheterocycloalkyl. In embodiments, Ring B is substituted (C₆-C₁₀) aryl.In embodiments, Ring B is substituted 5 to 10 membered heteroaryl. Inembodiments, Ring B is substituted (C₃-C₆) cycloalkyl. In embodiments,Ring B is substituted 3 to 6 membered heterocycloalkyl. In embodiments,Ring B is substituted phenyl. In embodiments, Ring B is substitutednaphthyl. In embodiments, Ring B is substituted 5 to 9 memberedheteroaryl. In embodiments, Ring B is substituted 5 to 6 memberedheteroaryl. In embodiments, Ring B is R⁴-substituted (C₃-C₁₀)cycloalkyl, R⁴-substituted 5 to 10 membered heterocycloalkyl,R⁴-substituted (C₆-C₁₀) aryl, or R⁴-substituted 5 to 10 memberedheteroaryl. In embodiments, Ring B is R⁴-substituted (C₃-C₁₀) cycloalkylor R⁴-substituted 5 to 10 membered heterocycloalkyl. In embodiments,Ring B is R⁴-substituted (C₃-C₁₀) cycloalkyl. In embodiments, Ring B isR⁴-substituted 3 to 10 membered heterocycloalkyl. In embodiments, Ring Bis R⁴-substituted (C₆-C₁₀) aryl. In embodiments, Ring B isR⁴-substituted 5 to 10 membered heteroaryl. In embodiments, Ring B isR⁴-substituted (C₃-C₆) cycloalkyl. In embodiments, Ring B isR⁴-substituted 3 to 6 membered heterocycloalkyl. In embodiments, Ring Bis R⁴-substituted phenyl. In embodiments, Ring B is R⁴-substitutednaphthyl. In embodiments, Ring B is R⁴-substituted 5 to 9 memberedheteroaryl. In embodiments, Ring B is R⁴-substituted 5 to 6 memberedheteroaryl. In embodiments, Ring B is R⁴-substituted thienyl. Inembodiments, Ring B is R⁴-substituted phenyl. In embodiments, Ring B isR⁴-substituted benzothienyl. In embodiments, Ring B is R⁴-substitutednaphthyl. In embodiments, Ring B is R⁴-substituted benzofuranyl. Inembodiments, Ring B is R⁴-substituted furanyl. In embodiments, Ring B isR⁴-substituted pyrrolyl. In embodiments, Ring B is R⁴-substituted2,3-dihydro-1H-indenyl.

In embodiments, Ring B is unsubstituted cycloalkyl. In embodiments, RingB is unsubstituted heterocycloalkyl. In embodiments, Ring B isunsubstituted aryl. In embodiments, Ring B is unsubstituted heteroaryl.In embodiments, Ring B is unsubstituted (C₃-C₁₀) cycloalkyl,unsubstituted 3 to 10 membered heterocycloalkyl, unsubstituted (C₆-C₁₀)aryl, or unsubstituted 5 to 10 membered heteroaryl. In embodiments, RingB is unsubstituted (C₃-C₁₀) cycloalkyl. In embodiments, Ring B isunsubstituted 3 to 10 membered heterocycloalkyl. In embodiments, Ring Bis unsubstituted (C₆-C₁₀) aryl. In embodiments, Ring B is unsubstituted5 to 10 membered heteroaryl. In embodiments, Ring B is unsubstituted(C₃-C₆) cycloalkyl. In embodiments, Ring B is unsubstituted 3 to 6membered heterocycloalkyl. In embodiments, Ring B is unsubstitutedphenyl. In embodiments, Ring B is unsubstituted naphthyl. Inembodiments, Ring B is unsubstituted 5 to 9 membered heteroaryl. Inembodiments, Ring B is unsubstituted 5 to 6 membered heteroaryl. Inembodiments, Ring B is unsubstituted (C₃-C₁₀) cycloalkyl, unsubstituted5 to 10 membered heterocycloalkyl, unsubstituted (C₆-C₁₀) aryl, orunsubstituted 5 to 10 membered heteroaryl. In embodiments, Ring B isunsubstituted (C₃-C₁₀) cycloalkyl or unsubstituted 5 to 10 memberedheterocycloalkyl. In embodiments, Ring B is unsubstituted (C₃-C₁₀)cycloalkyl. In embodiments, Ring B is unsubstituted 3 to 10 memberedheterocycloalkyl. In embodiments, Ring B is unsubstituted (C₆-C₁₀) aryl.In embodiments, Ring B is unsubstituted 5 to 10 membered heteroaryl. Inembodiments, Ring B is unsubstituted (C₃-C₆) cycloalkyl. In embodiments,Ring B is unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, Ring B is unsubstituted phenyl. In embodiments, Ring B isunsubstituted naphthyl. In embodiments, Ring B is unsubstituted 5 to 9membered heteroaryl. In embodiments, Ring B is unsubstituted 5 to 6membered heteroaryl. In embodiments, Ring B is unsubstituted thienyl. Inembodiments, Ring B is unsubstituted phenyl. In embodiments, Ring B isunsubstituted benzothienyl. In embodiments, Ring B is unsubstitutednaphthyl. In embodiments, Ring B is unsubstituted benzofuranyl. Inembodiments, Ring B is unsubstituted furanyl. In embodiments, Ring B isunsubstituted pyrrolyl. In embodiments, Ring B is unsubstituted2,3-dihydro-1H-indenyl. In embodiments, Ring B is unsubstituted phenyl.In embodiments, Ring B is

In embodiments, Ring B is

In embodiments, Ring B is

In embodiments, Ring B is

Ring B may be substituted with one R⁴. Ring B may be substituted withtwo optionally different R⁴ substituents. Ring B may be substituted withthree optionally different R⁴ substituents. Ring B may be substitutedwith four optionally different R⁴ substituents. Ring B may besubstituted with five optionally different R⁴ substituents. Ring B maybe substituted with six optionally different R⁴ substituents. Ring B maybe substituted with seven optionally different R⁴ substituents. Ring Bmay be substituted with eight optionally different R⁴ substituents. RingB may be substituted with nine optionally different R⁴ substituents.Ring B may be substituted with ten optionally different R⁴ substituents.

R⁴ is independently hydrogen, oxo, halogen, —CX^(a) ₃, —CN, —SO_(n1)R¹⁴,—SO_(v1)NR¹¹R¹², —NHNR¹¹R¹², —ONR¹¹R¹², —NHC═(O)NHNR¹¹R¹²,—NHC═(O)NR¹¹R¹², —N(O)^(m1), —NR¹¹R¹², —C(O)R¹³, —C(O)—OR¹³,—C(O)NR¹¹R¹², —OR¹⁴, NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³, —NR¹¹C(O)OR¹³,—NR¹¹OR¹³, —CHX^(a) ₂, —CH₂X^(a), —OCX^(a) ₃, —OCHX^(a) ₂, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R⁴ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R⁴ is unsubstituted methyl. In embodiments, R⁴ isunsubstituted ethyl. In embodiments, R⁴ is unsubstituted propyl. Inembodiments, R⁴ is unsubstituted methoxy. In embodiments, R⁴ isunsubstituted ethoxy. In embodiments, R⁴ is unsubstituted propoxy. Inembodiments, R⁴ is oxo. In embodiments, R⁴ is unsubstituted phenyl. Inembodiments, R⁴ is unsubstituted benzyl.

In embodiments, R⁴ is independently hydrogen, oxo,

halogen, —CX⁴ ₃, —CHX⁴ ₂, —OCH₂X⁴, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴ ₃, —OCHX⁴ ₂,R³⁹-substituted or unsubstituted alkyl, R³⁹-substituted or unsubstitutedheteroalkyl, R³⁹-substituted or unsubstituted cycloalkyl,R³⁹-substituted or unsubstituted heterocycloalkyl, R³⁹-substituted orunsubstituted aryl, or R³⁹-substituted or unsubstituted heteroaryl. X⁴is independently halogen. In embodiments, X⁴ is independently F or Cl.

In embodiments, R⁴ is R³⁹-substituted methyl. In embodiments, R⁴ isR³⁹-substituted ethyl. In embodiments, R⁴ is or substituted orunsubstituted 2 to 20 membered heteroalkyl. In embodiments, R⁴ is orsubstituted or unsubstituted 2 to 20 membered heteroalkyl. Inembodiments, R⁴ is or substituted or unsubstituted 2 to 15 memberedheteroalkyl. In embodiments, R⁴ is

wherein z is an integer from 1 to 10. In embodiments, R⁴ is

wherein z is an integer from 1 to 10. In embodiments, z is 1. Inembodiments, z is 2. In embodiments, z is 3. In embodiments, z is 4. Inembodiments, z is 5. In embodiments, z is 6. In embodiments, z is 7. Inembodiments, z is 8. In embodiments, z is 9. In embodiments, z is 10. Inembodiments, R⁴ is

R³⁹ is independently oxo,

halogen, —CX³⁹ ₃, —CHX³⁹ ₂, —OCH₂X³⁹, —OCHX³⁹ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —N₃,—OCX³⁹ ₃, —OCHX³⁹ ₂, R⁴⁰-substituted or unsubstituted alkyl,R⁴⁰-substituted or unsubstituted heteroalkyl, R⁴⁰-substituted orunsubstituted cycloalkyl, R⁴⁰-substituted or unsubstitutedheterocycloalkyl, R⁴⁰-substituted or unsubstituted aryl, orR⁴⁰-substituted or unsubstituted heteroaryl. X³⁹ is independentlyhalogen. In embodiments, X³⁹ is independently F or Cl.

In embodiments, R³⁹ is substituted or unsubstituted (C₁-C₅) alkyl,substituted or unsubstituted 2 to 5 membered heteroalkyl, substituted orunsubstituted (C₃-C₆) cycloalkyl, or substituted or unsubstituted 3 to 6membered heterocycloalkyl substituted or unsubstituted 3 to 6 memberedheterocycloalkyl or substituted or unsubstituted 5 to 6 memberedheteroaryl. In embodiments, R³⁹ is N₃. In embodiments, R³⁹ isunsubstituted phenyl. In embodiments, R³⁹ is unsubstituted benzyl.

R⁴⁰ is independently oxo,

halogen, —CX⁴⁰ ₃, —CHX⁴⁰ ₂, —OCH₂X⁴⁰, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —N₃,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁴⁰ ₃, —OCHX⁴⁰ ₂, R⁴¹-substituted or unsubstituted alkyl,R⁴¹-substituted or unsubstituted heteroalkyl, R⁴¹-substituted orunsubstituted cycloalkyl, R⁴¹-substituted or unsubstitutedheterocycloalkyl, R⁴¹-substituted or unsubstituted aryl, orR⁴¹-substituted or unsubstituted heteroaryl. X⁴⁰ is independentlyhalogen. In embodiments, X⁴⁰ is independently F or Cl. In embodiments,R⁴⁰ is N₃.

In embodiments, R⁴ is independently oxo,

halogen, —CX^(a) ₃, —CN, —SO_(n)R¹⁴, —SO_(v1)NR¹¹R¹², —NHNR¹¹R¹²,—ONR¹¹R¹², —NHC═(O)NHNR¹¹R¹², —NHC═(O)NR¹¹R¹², —N(O)^(m1), —NR¹¹R¹²,—C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)OR¹³, —NR¹¹OR¹³, —CHX^(a) ₂, —CH₂X^(a), —OCX^(a) ₃, —OCHX^(a)₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R⁴ is hydrogen. In embodiments, R⁴ is oxo. Inembodiments, R⁴ is independently halogen. In embodiments, R⁴ is —CX^(a)₃. In embodiments, R⁴ is —CN. In embodiments, R⁴ is —SO_(n1)R¹⁴. Inembodiments, R⁴ is —SO_(v1)NR¹¹R¹². In embodiments, R⁴ is —NHNR¹¹R¹². Inembodiments, R⁴ is —ONR¹¹R¹². In embodiments, R⁴ is —NHC═(O)NHNR¹¹R¹².In embodiments, R⁴ is —NHC═(O)NR¹¹R¹². In embodiments, R⁴ is —N(O)_(m1).In embodiments, R⁴ is —NR¹¹R¹². In embodiments, R⁴ is —C(O)R¹³. Inembodiments, R⁴ is —C(O)—OR¹³. In embodiments, R⁴ is —C(O)NR¹¹R¹². Inembodiments, R⁴ is —OR¹⁴. In embodiments, R⁴ is —NR¹¹SO₂R¹⁴. Inembodiments, R⁴ is —NR¹¹C═(O)R¹³. In embodiments, R⁴ is —NR¹¹C(O)OR¹³.In embodiments, R⁴ is —NR¹¹OR¹³. In embodiments, R⁴ is —CHX^(a) ₂. Inembodiments, R⁴ is —CH₂X^(a). In embodiments, R⁴ is —OCX^(a) ₃. Inembodiments, R⁴ is —OCHX^(a) ₂.

In embodiments, R⁴ is substituted or unsubstituted alkyl. Inembodiments, R⁴ is substituted or unsubstituted heteroalkyl. Inembodiments, R⁴ is substituted or unsubstituted cycloalkyl. Inembodiments, R⁴ is substituted or unsubstituted heterocycloalkyl. Inembodiments, R⁴ is substituted or unsubstituted aryl. In embodiments, R⁴is substituted or unsubstituted heteroaryl. In embodiments, R⁴ issubstituted alkyl. In embodiments, R⁴ is substituted heteroalkyl. Inembodiments, R⁴ is substituted cycloalkyl. In embodiments, R⁴ issubstituted heterocycloalkyl. In embodiments, R⁴ is substituted aryl. Inembodiments, R⁴ is substituted heteroaryl. In embodiments, R⁴ isunsubstituted alkyl. In embodiments, R⁴ is unsubstituted heteroalkyl. Inembodiments, R⁴ is unsubstituted cycloalkyl. In embodiments, R⁴ isunsubstituted heterocycloalkyl. In embodiments, R⁴ is unsubstitutedaryl. In embodiments, R⁴ is unsubstituted heteroaryl.

In embodiments, R⁴ is independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R⁴ is independently halogen, —CF₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—CHF₂, —CH₂F, —OCF₃, —OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl,or substituted or unsubstituted 2 to 5 membered heteroalkyl. Inembodiments, R⁴ is methyl.

In embodiments, R⁴ is independently

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R⁴ is independently halogen. Inembodiments, R⁴ is independently —CF₃. In embodiments, R⁴ isindependently —CN. In embodiments, R⁴ is independently —OH. Inembodiments, R⁴ is independently —NH₂. In embodiments, R⁴ isindependently —COOH. In embodiments, R⁴ is independently —CONH₂. Inembodiments, R⁴ is independently —NO₂. In embodiments, R⁴ isindependently —SH. In embodiments, R⁴ is independently —SO₃H. Inembodiments, R⁴ is independently —SO₄H. In embodiments, R⁴ isindependently —SO₂NH₂. In embodiments, R⁴ is independently —NHNH₂. Inembodiments, R⁴ is independently —ONH₂. In embodiments, R⁴ isindependently —NHC═(O)NHNH₂. In embodiments, R⁴ is independently—NHC═(O)NH₂. In embodiments, R⁴ is independently —NHSO₂H. Inembodiments, R⁴ is independently —NHC═(O)H. In embodiments, R⁴ isindependently —NHC(O)OH. In embodiments, R⁴ is independently —NHOH. Inembodiments, R⁴ is independently —CHF₂. In embodiments, R⁴ isindependently —CH₂F. In embodiments, R⁴ is independently —OCF₃. Inembodiments, R⁴ is independently —OCHF₂.

In embodiments, R⁴ is independently substituted or unsubstituted (C₁-C₅)alkyl. In embodiments, R⁴ is independently substituted or unsubstituted2 to 5 membered heteroalkyl. In embodiments, R⁴ is independentlysubstituted (C₁-C₅) alkyl. In embodiments, R⁴ is independentlysubstituted 2 to 5 membered heteroalkyl. In embodiments, R⁴ isindependently unsubstituted (C₁-C₅) alkyl. In embodiments, R⁴ isindependently unsubstituted 2 to 5 membered heteroalkyl. In embodiments,R⁴ is independently substituted or unsubstituted butyl. In embodiments,R⁴ is independently substituted or unsubstituted butoxy. In embodiments,R⁴ is independently substituted butyl. In embodiments, R⁴ isindependently substituted butoxy. In embodiments, R⁴ is independentlyunsubstituted butyl. In embodiments, R⁴ is independently unsubstitutedbutoxy. In embodiments, R⁴ is independently substituted or unsubstitutedpropyl. In embodiments, R⁴ is independently substituted or unsubstitutedpropoxy. In embodiments, R⁴ is independently substituted propyl. Inembodiments, R⁴ is independently substituted propoxy. In embodiments, R⁴is independently unsubstituted propyl. In embodiments, R⁴ isindependently unsubstituted propoxy. In embodiments, R⁴ is independentlysubstituted or unsubstituted ethyl. In embodiments, R⁴ is independentlysubstituted or unsubstituted ethoxy. In embodiments, R⁴ is independentlysubstituted ethyl. In embodiments, R⁴ is independently substitutedethoxy. In embodiments, R⁴ is independently unsubstituted ethyl. Inembodiments, R⁴ is independently unsubstituted ethoxy. In embodiments,R⁴ is independently substituted or unsubstituted methyl. In embodiments,R⁴ is independently substituted or unsubstituted methoxy. Inembodiments, R⁴ is independently substituted methyl. In embodiments, R⁴is independently substituted methoxy. In embodiments, R⁴ isindependently unsubstituted methyl. In embodiments, R⁴ is independentlyunsubstituted methoxy. In embodiments, R⁴ is independently hydrogen. Inembodiments, R⁴ is independently unsubstituted methoxy. In embodiments,R⁴ is independently halogen. In embodiments, R⁴ is F.

In embodiments, two adjacent R⁴ substituents are joined to form asubstituted or unsubstituted cycloalkyl. In embodiments, two adjacent R⁴substituents are joined to form a substituted or unsubstitutedheterocycloalkyl. In embodiments, two adjacent R⁴ substituents arejoined to form a substituted or unsubstituted aryl. In embodiments, twoadjacent R⁴ substituents are joined to form a substituted orunsubstituted heteroaryl. In embodiments, two adjacent R⁴ substituentsare joined to form a substituted or unsubstituted (C₃-C₆) cycloalkyl. Inembodiments, two adjacent R⁴ substituents are joined to form asubstituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, two adjacent R⁴ substituents are joined to form asubstituted or unsubstituted (C₆-C₁₀) aryl. In embodiments, two adjacentR⁴ substituents are joined to form a substituted or unsubstituted 5 to10 membered heteroaryl. In embodiments, two adjacent R⁴ substituents arejoined to form a substituted or unsubstituted phenyl. In embodiments,two adjacent R⁴ substituents are joined to form a substituted orunsubstituted 5 to 9 membered heteroaryl. In embodiments, two adjacentR⁴ substituents are joined to form a substituted or unsubstitutednaphthyl. In embodiments, two adjacent R⁴ substituents are joined toform a substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, two adjacent R⁴ substituents are joined to form asubstituted cycloalkyl. In embodiments, two adjacent R⁴ substituents arejoined to form a substituted heterocycloalkyl. In embodiments, twoadjacent R⁴ substituents are joined to form a substituted aryl. Inembodiments, two adjacent R⁴ substituents are joined to form asubstituted heteroaryl. In embodiments, two adjacent R⁴ substituents arejoined to form a substituted (C₃-C₆) cycloalkyl. In embodiments, twoadjacent R⁴ substituents are joined to form a substituted 3 to 6membered heterocycloalkyl. In embodiments, two adjacent R⁴ substituentsare joined to form a substituted (C₆-C₁₀) aryl. In embodiments, twoadjacent R⁴ substituents are joined to form a substituted 5 to 10membered heteroaryl. In embodiments, two adjacent R⁴ substituents arejoined to form a substituted phenyl. In embodiments, two adjacent R⁴substituents are joined to form a substituted 5 to 9 memberedheteroaryl. In embodiments, two adjacent R⁴ substituents are joined toform a substituted naphthyl. In embodiments, two adjacent R⁴substituents are joined to form a substituted 5 to 6 memberedheteroaryl. In embodiments, two adjacent R⁴ substituents are joined toform an unsubstituted cycloalkyl. In embodiments, two adjacent R⁴substituents are joined to form an unsubstituted heterocycloalkyl. Inembodiments, two adjacent R⁴ substituents are joined to form anunsubstituted aryl. In embodiments, two adjacent R⁴ substituents arejoined to form an unsubstituted heteroaryl. In embodiments, two adjacentR⁴ substituents are joined to form an unsubstituted (C₃-C₆) cycloalkyl.In embodiments, two adjacent R⁴ substituents are joined to form anunsubstituted 3 to 6 membered heterocycloalkyl. In embodiments, twoadjacent R⁴ substituents are joined to form an unsubstituted (C₆-C₁₀)aryl. In embodiments, two adjacent R⁴ substituents are joined to form anunsubstituted 5 to 10 membered heteroaryl. In embodiments, two adjacentR⁴ substituents are joined to form an unsubstituted phenyl. Inembodiments, two adjacent R⁴ substituents are joined to form anunsubstituted 5 to 9 membered heteroaryl. In embodiments, two adjacentR⁴ substituents are joined to form an unsubstituted naphthyl. Inembodiments, two adjacent R⁴ substituents are joined to form anunsubstituted 5 to 6 membered heteroaryl.

R¹¹, R¹², R¹³, and R¹⁴ are independently hydrogen, halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹¹and R¹² substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; m1 and v1 are independently 1or 2; n1 is independently an integer from 0 to 4; X^(a) is independently—Cl, —Br, —I, or —F.

Each R¹¹ and R¹² substituents bonded to the same nitrogen atom may bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl. Each R¹¹ and R¹² substituentsbonded to the same nitrogen atom may be joined to form an unsubstitutedheterocycloalkyl or unsubstituted heteroaryl. Each R¹¹ and R¹²substituents bonded to the same nitrogen atom may be joined to form asubstituted or unsubstituted 4 to 6 membered heterocycloalkyl orsubstituted or unsubstituted 5 to 6 membered heteroaryl. Each R¹¹ andR¹² substituents bonded to the same nitrogen atom may be joined to forman unsubstituted 4 to 6 membered heterocycloalkyl or unsubstituted 5 to6 membered heteroaryl.

In embodiments, R¹¹ is independently hydrogen, oxo,

halogen, —CX¹¹ ₃, —CHX¹¹ ₂, —OCH₂X¹¹, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹¹ ₃, —OCHX¹¹ ₂,R⁶⁰-substituted or unsubstituted alkyl, R⁶⁰-substituted or unsubstitutedheteroalkyl, R⁶⁰-substituted or unsubstituted cycloalkyl, R⁶⁰substituted or unsubstituted heterocycloalkyl, R⁶⁰-substituted orunsubstituted aryl, or R⁶⁰-substituted or unsubstituted heteroaryl. X¹¹is independently halogen. In embodiments, X¹¹ is independently F or Cl.

R⁶⁰ is independently oxo,

halogen, —CX⁶⁰ ₃, —CHX⁶⁰ ₂, —OCH₂X⁶⁰, —OCHX⁶⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁶⁰ ₃, —OCHX⁶⁰ ₂, R⁶¹-substituted or unsubstituted alkyl,R⁶¹-substituted or unsubstituted heteroalkyl, R⁶¹-substituted orunsubstituted cycloalkyl, R⁶¹-substituted or unsubstitutedheterocycloalkyl, R⁶¹-substituted or unsubstituted aryl, orR⁶¹-substituted or unsubstituted heteroaryl. X⁶⁰ is independentlyhalogen. In embodiments, X⁶⁰ is independently F or Cl.

R⁶¹ is independently oxo,

halogen, —CX⁶¹ ₃, —CHX⁶¹ ₂, —OCH₂X⁶¹, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁶¹ ₃, —OCHX⁶¹ ₂,R⁶²-substituted or unsubstituted alkyl, R⁶²-substituted or unsubstitutedheteroalkyl, R⁶²-substituted or unsubstituted cycloalkyl, R⁶²substituted or unsubstituted heterocycloalkyl, R⁶²-substituted orunsubstituted aryl, or R⁶²-substituted or unsubstituted heteroaryl. X⁶¹is independently halogen. In embodiments, X⁶¹ is independently F or Cl.

In embodiments, R¹² is independently hydrogen, oxo,

halogen, —CX¹² ₃, —CHX¹² ₂, —OCH₂X¹², —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹² ₃, —OCHX¹² ₂,R⁶³-substituted or unsubstituted alkyl, R⁶³-substituted or unsubstitutedheteroalkyl, R⁶³-substituted or unsubstituted cycloalkyl, R⁶³substituted or unsubstituted heterocycloalkyl, R⁶³-substituted orunsubstituted aryl, or R⁶³-substituted or unsubstituted heteroaryl. X¹²is independently halogen. In embodiments, X¹² is independently F or Cl.

R⁶³ is independently oxo,

halogen, —CX⁶³ ₃, —CHX⁶³ ₂, —OCH₂X⁶³, —OCHX⁶³ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁶³ ₃, —OCHX⁶³ ₂, R⁶⁴-substituted or unsubstituted alkyl,R⁶⁴-substituted or unsubstituted heteroalkyl, R⁶⁴-substituted orunsubstituted cycloalkyl, R⁶⁴-substituted or unsubstitutedheterocycloalkyl, R⁶⁴-substituted or unsubstituted aryl, orR⁶⁴-substituted or unsubstituted heteroaryl. X⁶³ is independentlyhalogen. In embodiments, X⁶³ is independently F or Cl.

R⁶⁴ is independently oxo,

halogen, —CX⁶⁴ ₃, —CHX⁶⁴ ₂, —OCH₂X⁶⁴, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁶⁴ ₃, —OCHX⁶⁴ ₂,R⁶⁵-substituted or unsubstituted alkyl, R⁶⁵-substituted or unsubstitutedheteroalkyl, R⁶⁵-substituted or unsubstituted cycloalkyl, R⁶⁵substituted or unsubstituted heterocycloalkyl, R⁶⁵-substituted orunsubstituted aryl, or R⁶⁵-substituted or unsubstituted heteroaryl. X⁶⁴is independently halogen. In embodiments, X⁶⁴ is independently F or Cl.

In embodiments, R¹³ is independently hydrogen, oxo,

halogen, —CX¹³ ₃, —CHX¹³ ₂, —OCH₂X¹³, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹³ ₃, —OCHX¹³ ₂,R⁶⁶-substituted or unsubstituted alkyl, R⁶⁶-substituted or unsubstitutedheteroalkyl, R⁶⁶-substituted or unsubstituted cycloalkyl, R⁶⁶substituted or unsubstituted heterocycloalkyl, R⁶⁶-substituted orunsubstituted aryl, or R⁶⁶-substituted or unsubstituted heteroaryl. X¹³is independently halogen. In embodiments, X¹³ is independently F or Cl.

R⁶⁶ is independently oxo,

halogen, —CX⁶⁶ ₃, —CHX⁶⁶ ₂, —OCH₂X⁶⁶, —OCHX⁶⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁶⁶ ₃, —OCHX⁶⁶ ₂, R⁶⁷-substituted or unsubstituted alkyl,R⁶⁷-substituted or unsubstituted heteroalkyl, R⁶⁷-substituted orunsubstituted cycloalkyl, R⁶⁷-substituted or unsubstitutedheterocycloalkyl, R⁶⁷-substituted or unsubstituted aryl, orR⁶⁷-substituted or unsubstituted heteroaryl. X⁶⁶ is independentlyhalogen. In embodiments, X⁶⁶ is independently F or Cl.

R⁶⁷ is independently oxo,

halogen, —CX⁶⁷ ₃, —CHX⁶⁷ ₂, —OCH₂X⁶⁷, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁶⁷ ₃, —OCHX⁶⁷ ₂,R⁶⁸-substituted or unsubstituted alkyl, R⁶⁸-substituted or unsubstitutedheteroalkyl, R⁶⁸-substituted or unsubstituted cycloalkyl, R⁶⁸substituted or unsubstituted heterocycloalkyl, R⁶⁸-substituted orunsubstituted aryl, or R⁶⁸-substituted or unsubstituted heteroaryl. X⁶⁷is independently halogen. In embodiments, X⁶⁷ is independently F or Cl.

In embodiments, R¹⁴ is independently hydrogen, oxo,

halogen, —CX¹⁴ ₃, —CHX¹⁴ ₂, —OCH₂X¹⁴, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹⁴ ₃, —OCHX¹⁴ ₂,R⁶⁹-substituted or unsubstituted alkyl, R⁶⁹-substituted or unsubstitutedheteroalkyl, R⁶⁹-substituted or unsubstituted cycloalkyl, R⁶⁹substituted or unsubstituted heterocycloalkyl, R⁶⁹-substituted orunsubstituted aryl, or R⁶⁹-substituted or unsubstituted heteroaryl. X¹⁴is independently halogen. In embodiments, X¹⁴ is independently F or Cl.

R⁶⁹ is independently oxo,

halogen, —CX⁶⁹ ₃, —CHX⁶⁹ ₂, —OCH₂X⁶⁹, —OCHX⁶⁹ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁶⁹ ₃, —OCHX⁶⁹ ₂, R⁷⁰-substituted or unsubstituted alkyl,R⁷⁰-substituted or unsubstituted heteroalkyl, R⁷⁰-substituted orunsubstituted cycloalkyl, R⁷⁰-substituted or unsubstitutedheterocycloalkyl, R⁷⁰-substituted or unsubstituted aryl, orR⁷⁰-substituted or unsubstituted heteroaryl. X⁶⁹ is independentlyhalogen. In embodiments, X⁶⁹ is independently F or Cl.

R⁷⁰ is independently oxo,

halogen, —CX⁷⁰ ₃, —CHX⁷⁰ ₂, —OCH₂X⁷⁰, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁷⁰ ₃, —OCHX⁷⁰ ₂,R⁷¹-substituted or unsubstituted alkyl, R⁷¹-substituted or unsubstitutedheteroalkyl, R⁷¹-substituted or unsubstituted cycloalkyl, R⁷¹substituted or unsubstituted heterocycloalkyl, R⁷¹-substituted orunsubstituted aryl, or R⁷¹-substituted or unsubstituted heteroaryl. X⁷⁰is independently halogen. In embodiments, X⁷⁰ is independently F or Cl.

Each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ may independently behydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. Each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴may independently be hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

Each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ may independently behydrogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, orunsubstituted heteroaryl. Each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴may independently be hydrogen, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted 2 to 8 membered heteroalkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8membered heterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Each R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ may independently be hydrogen,unsubstituted C₁-C₈ alkyl, unsubstituted 2 to 8 membered heteroalkyl,unsubstituted C₃-C₈ cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted C₆-C₁₀ aryl, or unsubstituted 5 to 10membered heteroaryl.

Each R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ may independently behydrogen, substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstitutedC₃-C₆ cycloalkyl, substituted or unsubstituted 3 to 6 memberedheterocycloalkyl, substituted or unsubstituted C₆ aryl, or substitutedor unsubstituted 5 to 6 membered heteroaryl. Each R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, and R¹⁴ may independently be hydrogen, unsubstituted C₁-C₆alkyl, unsubstituted 2 to 6 membered heteroalkyl, unsubstituted C₃-C₆cycloalkyl, unsubstituted 3 to 6 membered heterocycloalkyl,unsubstituted C₆ aryl, or unsubstituted 5 to 6 membered heteroaryl.

In embodiments, Ring A is unsubstituted phenyl and Ring B isunsubstituted thienyl. In embodiments, Ring A is para-hydroxysubstituted phenyl and Ring B is unsubstituted thienyl. In embodiments,Ring A is para-hydroxy substituted phenyl and Ring B is unsubstitutedphenyl. In embodiments, Ring A is para-hydroxy substituted phenyl andRing B is unsubstituted benzothienyl. In embodiments, Ring A ispara-hydroxy substituted phenyl and Ring B is para-methyl substitutedphenyl. In embodiments, Ring A is 2-hydroxy pyridin-4-yl and Ring B isunsubstituted thienyl. In embodiments, Ring A is 2-hydroxy pyridin-5-yland Ring B is unsubstituted thienyl. In embodiments, Ring A ispara-hydroxy substituted phenyl and Ring B is unsubstituted napththyl.In embodiments, Ring A is para-hydroxy substituted phenyl and Ring B isunsubstituted 2,3-dihydro-1H-indenyl.

In embodiments, L¹ is substituted or unsubstituted (C₁-C₅) alkylene. Inembodiments, L¹ is substituted or unsubstituted 2 to 5 memberedheteroalkylene. In embodiments, L¹ is unsubstituted (C₁-C₃) alkylene. Inembodiments, L¹ is R⁹⁶-substituted or unsubstituted C₁-C₅ alkylene,R⁹⁶-substituted or unsubstituted 2 to 5 membered heteroalkylene. Inembodiments, L¹ is R⁹⁶-substituted or unsubstituted C₁-C₅ alkylene. Inembodiments, L¹ is R⁹⁶-substituted or unsubstituted C₁-C₃ alkylene. Inembodiments, L¹ is R⁹⁶-substituted or unsubstituted methylene. Inembodiments, L¹ is R⁹⁶-substituted or unsubstituted 2 to 5 memberedheteroalkylene. In embodiments, L¹ is R⁹⁶-substituted or unsubstituted 2to 3 membered heteroalkylene. In embodiments, L¹ is unsubstitutedmethylene. In embodiments, L¹ and R¹ are joined to form a substituted orunsubstituted 4 to 8 membered heterocycloalkyl. In embodiments, L¹ andR¹ are joined to form an R⁹⁶-substituted or unsubstituted 4 to 8membered heterocycloalkyl. In embodiments, L¹ and R¹ are joined to forma substituted 4 to 8 membered heterocycloalkyl. In embodiments, L¹ andR¹ are joined to form an R⁹⁶-substituted 4 to 8 memberedheterocycloalkyl. In embodiments, L¹ and R¹ are joined to form anunsubstituted 4 to 8 membered heterocycloalkyl. In embodiments, L¹ andR¹ are joined to form a substituted or unsubstituted 4 memberedheterocycloalkyl. In embodiments, L¹ and R¹ are joined to form anR⁹⁶-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, L⁹ and R¹ are joined to form a substituted 4 memberedheterocycloalkyl. In embodiments, L¹ and R¹ are joined to form an R⁹⁶substituted 4 membered heterocycloalkyl. In embodiments, L¹ and R¹ arejoined to form an unsubstituted 4 membered heterocycloalkyl. Inembodiments, L¹ and R¹ are joined to form a substituted or unsubstituted4 membered heterocycloalkyl. In embodiments, L¹ and R¹ are joined toform an R⁹⁶-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, L¹ and R¹ are joined to form a substituted 5 memberedheterocycloalkyl. In embodiments, L and R¹ are joined to form anR⁹⁶-substituted 5 membered heterocycloalkyl. In embodiments, L¹ and R¹are joined to form an unsubstituted 5 membered heterocycloalkyl. Inembodiments, L¹ and R are joined to form a substituted or unsubstituted4 membered heterocycloalkyl. In embodiments, L¹ and R¹ are joined toform an R⁹⁶-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, L¹ and R¹ are joined to form a substituted 6 memberedheterocycloalkyl. In embodiments, L¹ and R¹ are joined to form anR⁹⁶-substituted 6 membered heterocycloalkyl. In embodiments, L¹ and R¹are joined to form an unsubstituted 6 membered heterocycloalkyl. Inembodiments, L¹ and R¹ are joined to form a substituted or unsubstituted4 membered heterocycloalkyl. In embodiments, L¹ and R¹ are joined toform an R⁹⁶-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, L¹ and R¹ are joined to form a substituted 7 memberedheterocycloalkyl. In embodiments, L¹ and R¹ are joined to form an R⁹⁶substituted 7 membered heterocycloalkyl. In embodiments, L¹ and R¹ arejoined to form an unsubstituted 7 membered heterocycloalkyl. Inembodiments, L¹ and R¹ are joined to form a substituted or unsubstituted4 membered heterocycloalkyl. In embodiments, L¹ and R¹ are joined toform an R⁹⁶-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, L and R¹ are joined to form a substituted 8 memberedheterocycloalkyl. In embodiments, L¹ and R¹ are joined to form anR⁹⁶-substituted 8 membered heterocycloalkyl. In embodiments, L¹ and R¹are joined to form an unsubstituted 8 membered heterocycloalkyl.

In embodiments, L¹ and R² are joined to form a substituted orunsubstituted 4 to 8 membered heterocycloalkyl. In embodiments, L¹ andR² are joined to form an R⁹⁶-substituted or unsubstituted 4 to 8membered heterocycloalkyl. In embodiments, L¹ and R² are joined to forma substituted 4 to 8 membered heterocycloalkyl. In embodiments, L¹ andR² are joined to form an R⁹⁶-substituted 4 to 8 memberedheterocycloalkyl. In embodiments, L¹ and R² are joined to form anunsubstituted 4 to 8 membered heterocycloalkyl. In embodiments, L¹ andR² are joined to form a substituted or unsubstituted 4 memberedheterocycloalkyl. In embodiments, L¹ and R² are joined to form anR⁹⁶-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, L¹ and R² are joined to form a substituted 4 memberedheterocycloalkyl. In embodiments, L¹ and R² are joined to form anR⁹⁶-substituted 4 membered heterocycloalkyl. In embodiments, L¹ and R²are joined to form an unsubstituted 4 membered heterocycloalkyl. Inembodiments, L¹ and R² are joined to form a substituted or unsubstituted4 membered heterocycloalkyl. In embodiments, L¹ and R² are joined toform an R⁹⁶-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, L¹ and R² are joined to form a substituted 5 memberedheterocycloalkyl. In embodiments, L¹ and R² are joined to form anR⁹⁶⁻substituted 5 membered heterocycloalkyl. In embodiments, L¹ and R²are joined to form an unsubstituted 5 membered heterocycloalkyl. Inembodiments, L¹ and R² are joined to form a substituted or unsubstituted4 membered heterocycloalkyl. In embodiments, L¹ and R² are joined toform an R⁹⁶-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, L¹ and R² are joined to form a substituted 6 memberedheterocycloalkyl. In embodiments, L¹ and R² are joined to form anR⁹⁶-substituted 6 membered heterocycloalkyl. In embodiments, L¹ and R²are joined to form an unsubstituted 6 membered heterocycloalkyl. Inembodiments, L¹ and R² are joined to form a substituted or unsubstituted4 membered heterocycloalkyl. In embodiments, L¹ and R² are joined toform an R⁹⁶-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, L and R² are joined to form a substituted 7 memberedheterocycloalkyl. In embodiments, L¹ and R² are joined to form anR⁹⁶-substituted 7 membered heterocycloalkyl. In embodiments, L¹ and R²are joined to form an unsubstituted 7 membered heterocycloalkyl. Inembodiments, L¹ and R² are joined to form a substituted or unsubstituted4 membered heterocycloalkyl. In embodiments, L¹ and R² are joined toform an R⁹⁶-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, L¹ and R² are joined to form a substituted 8 memberedheterocycloalkyl. In embodiments, L¹ and R² are joined to form anR⁹⁶-substituted 8 membered heterocycloalkyl. In embodiments, L¹ and R²are joined to form an unsubstituted 8 membered heterocycloalkyl.

In embodiments, L¹ is a bond, R⁹⁶-substituted or unsubstituted alkylene,or R⁹⁶-substituted or unsubstituted heteroalkylene.

R⁹⁶ is independently oxo,

halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —OCH₂X⁹⁶, —OCHX⁹⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁹⁶ ₃, —OCHX⁹⁶ ₂, R⁹⁷-substituted or unsubstituted alkyl,R⁹⁷-substituted or unsubstituted heteroalkyl, R⁹⁷-substituted orunsubstituted cycloalkyl, R⁹⁷-substituted or unsubstitutedheterocycloalkyl, R⁹⁷-substituted or unsubstituted aryl, orR⁹⁷-substituted or unsubstituted heteroaryl. X⁹⁶ is independentlyhalogen. In embodiments, X⁹⁶ is independently F or Cl.

R⁹⁷ is independently oxo,

halogen, —CX⁹⁷ ₃, —CHX⁹⁷ ₂, —OCH₂X⁹⁷, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹⁷ ₃, —OCHX⁹⁷ ₂,R⁹⁸-substituted or unsubstituted alkyl, R⁹⁸-substituted or unsubstitutedheteroalkyl, R⁹⁸-substituted or unsubstituted cycloalkyl, R⁹⁸substituted or unsubstituted heterocycloalkyl, R⁹⁸-substituted orunsubstituted aryl, or R⁹⁸-substituted or unsubstituted heteroaryl. X⁹⁷is independently halogen. In embodiments, X⁹⁷ is independently F or Cl.

In embodiments, L² is a bond, R⁹⁹-substituted or unsubstituted alkylene,or R⁹⁹ substituted or unsubstituted heteroalkylene.

R⁹⁹ is independently oxo,

halogen, —CX⁹⁹ ₃, —CHX⁹⁹ ₂, —OCH₂X⁹⁹, —OCHX⁹⁹ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁹⁹ ₃, —OCHX⁹⁹ ₂, R¹⁰⁰-substituted or unsubstituted alkyl,R¹⁰⁰-substituted or unsubstituted heteroalkyl, R¹⁰⁰-substituted orunsubstituted cycloalkyl, R¹⁰⁰-substituted or unsubstitutedheterocycloalkyl, R¹⁰⁰-substituted or unsubstituted aryl, orR¹⁰⁰-substituted or unsubstituted heteroaryl. X⁹⁹ is independentlyhalogen. In embodiments, X⁹⁹ is independently F or Cl.

R¹⁰⁰ is independently oxo,

halogen, —CX¹⁰⁰ ₃, —CHX¹⁰⁰ ₂, —OCH₂X¹⁰⁰, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹⁰⁰ ₃, —OCHX¹⁰⁰₂, R¹⁰¹-substituted or unsubstituted alkyl, R¹⁰¹-substituted orunsubstituted heteroalkyl, R¹⁰¹-substituted or unsubstituted cycloalkyl,R¹⁰¹-substituted or unsubstituted heterocycloalkyl, R¹⁰¹-substituted orunsubstituted aryl, or R¹⁰¹-substituted or unsubstituted heteroaryl.X¹⁰⁰ is independently halogen. In embodiments, X¹⁰⁰ is independently For Cl.

In embodiments, R⁹⁶ is independently oxo,

halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —OCH₂X⁹⁶, —OCHX⁹⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹⁶ ₃, —OCHX⁹⁶ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. X⁹⁶ is independently halogen.

In embodiments, R¹ is independently hydrogen, oxo,

halogen, —CX¹³, —CHX¹², —OCH₂X¹, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX¹ ₃, —OCHX¹ ₂,R³⁰-substituted or unsubstituted alkyl, R³⁰-substituted or unsubstitutedheteroalkyl, R³⁰-substituted or unsubstituted cycloalkyl, R³⁰substituted or unsubstituted heterocycloalkyl, R³⁰-substituted orunsubstituted aryl, or R³⁰-substituted or unsubstituted heteroaryl. X¹is independently halogen. In embodiments, X¹ is independently F or Cl.

R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX³⁰ ₃, —OCHX³⁰ ₂, R³¹-substituted or unsubstituted alkyl,R³¹-substituted or unsubstituted heteroalkyl, R³¹-substituted orunsubstituted cycloalkyl, R³¹-substituted or unsubstitutedheterocycloalkyl, R³¹-substituted or unsubstituted aryl, orR³¹-substituted or unsubstituted heteroaryl. X³⁰ is independentlyhalogen. In embodiments, X³⁰ is independently F or Cl.

R³¹ is independently oxo,

halogen, —CX³¹ ₃, —CHX³¹ ₂, —OCH₂X³¹, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³¹ ₃, —OCHX³¹ ₂,R³²-substituted or unsubstituted alkyl, R³²-substituted or unsubstitutedheteroalkyl, R³²-substituted or unsubstituted cycloalkyl, R³²substituted or unsubstituted heterocycloalkyl, R³²-substituted orunsubstituted aryl, or R³²-substituted or unsubstituted heteroaryl. X³¹is independently halogen. In embodiments, X³¹ is independently F or Cl.

In embodiments, R¹ is independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹ is independently halogen, —CF₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃,—OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted(C₃-C₆) cycloalkyl, or substituted or unsubstituted 3 to 6 memberedheterocycloalkyl.

In embodiments, R¹ is independently

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, R³⁰-substituted orunsubstituted (C₁-C₅) alkyl, R³⁰-substituted or unsubstituted 2 to 5membered heteroalkyl, R³⁰-substituted or unsubstituted (C₃-C₆)cycloalkyl, or R³⁰-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R¹ is unsubstituted (C₁-C₃) alkyl. Inembodiments, R¹ is unsubstituted (C₁-C₂) alkyl. In embodiments, R¹ isR³⁰-substituted or unsubstituted (C₁-C₂) alkyl; R³⁰ is independentlyhalogen, —OH, —NH₂, —SH, substituted or unsubstituted (C₁-C₃) alkyl,substituted or unsubstituted 2 to 3 membered heteroalkyl, or substitutedor unsubstituted cyclopropyl; and X³⁰ is independently halogen. Inembodiments, R¹ is unsubstituted methyl. In embodiments, R¹ isR³⁰-substituted or unsubstituted (C₁-C₃) alkyl or R³⁰-substituted orunsubstituted 2 to 3 membered heteroalkyl. In embodiments, R¹ isindependently hydrogen. In embodiments, R¹ is a R³⁰-substituted methyl.In embodiments, R¹ is a R³⁰-substituted ethyl. In embodiments, R¹ isR³⁰-substituted or unsubstituted 2 to 5 membered heteroalkyl. Inembodiments, R¹ is R³⁰-substituted or unsubstituted 3 memberedheteroalkyl. In embodiments, R¹ is R³⁰-substituted or unsubstituted 2 to5 membered heteroalkyl. In embodiments, R¹ is 9-ethyl-9H-fluorene. Inembodiments, R¹ is 9-fluoromethoxycarbonyl. In embodiments, R¹ is

In embodiments, R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³⁰ ₃, —OCHX³⁰ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. X³⁰ is independently halogen.In embodiments, R³⁰ is —Cl. In embodiments, R³⁰ is —OH.

In embodiments, R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHOH, —OCX³⁰ ₃, —OCHX³⁰ ₂,substituted or unsubstituted (C₁-C₃) alkyl, substituted or unsubstituted2 to 3 membered heteroalkyl, or substituted or unsubstitutedcyclopropyl. X³⁰ is independently halogen. In embodiments, R³⁰ isunsubstituted cyclopropyl. In embodiments, R³⁰ is unsubstitutedcyclobutyl. In embodiments, R³⁰ is unsubstituted cyclopentyl. Inembodiments, R³⁰ is unsubstituted cyclohexyl. In embodiments, R³⁰ issubstituted or unsubstituted phenyl. In embodiments, R³⁰ isunsubstituted phenyl. In embodiments, R³⁰ is unsubstituted benzyl.

In embodiments, R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³⁰ ₃, —OCHX³⁰ ₂,substituted or unsubstituted (C₁-C₃) alkyl, or substituted orunsubstituted 2 to 3 membered heteroalkyl. In embodiments, R³⁰ isindependently oxo, halogen, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,substituted or unsubstituted (C₁-C₃) alkyl, or substituted orunsubstituted 2 to 3 membered heteroalkyl. X³⁰ is independently halogen.

In embodiments, R² is independently hydrogen, oxo,

halogen, —CX² ₃, —CHX² ₂, —OCH₂X², —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX² ₃, —OCHX² ₂,R³³-substituted or unsubstituted alkyl, R³³-substituted or unsubstitutedheteroalkyl, R³³-substituted or unsubstituted cycloalkyl,R³³-substituted or unsubstituted heterocycloalkyl, R³³-substituted orunsubstituted aryl, or R³³-substituted or unsubstituted heteroaryl. X²is independently halogen. In embodiments, X² is independently F or Cl.

R³³ is independently oxo,

halogen, —CX³³ ₃, —CHX³³ ₂, —OCH₂X³³, —OCHX³³ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX³³ ₃, —OCHX³³ ₂, R³⁴-substituted or unsubstituted alkyl,R³⁴-substituted or unsubstituted heteroalkyl, R³⁴-substituted orunsubstituted cycloalkyl, R³⁴-substituted or unsubstitutedheterocycloalkyl, R³⁴-substituted or unsubstituted aryl, orR³⁴-substituted or unsubstituted heteroaryl. X³³ is independentlyhalogen. In embodiments, X³³ is independently F or Cl.

R³⁴ is independently oxo,

halogen, —CX³⁴ ₃, —CHX³⁴ ₂, —OCH₂X³⁴, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³⁴ ₃, —OCHX³⁴ ₂,R³⁵-substituted or unsubstituted alkyl, R³⁵-substituted or unsubstitutedheteroalkyl, R³⁵-substituted or unsubstituted cycloalkyl,R³⁵-substituted or unsubstituted heterocycloalkyl, R³⁵-substituted orunsubstituted aryl, or R³⁵-substituted or unsubstituted heteroaryl. X³⁴is independently halogen. In embodiments, X³⁴ is independently F or Cl.

In embodiments, R² is independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R² is independentlyhalogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

In embodiments, R² is independently

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, R³³-substituted orunsubstituted (C₁-C₅) alkyl, R³³-substituted or unsubstituted 2 to 5membered heteroalkyl, R³³-substituted or unsubstituted (C₃-C₆)cycloalkyl, or R³³-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R² is R³³-substituted or unsubstituted(C₁-C₃) alkyl or R³³ substituted or unsubstituted 2 to 3 memberedheteroalkyl. In embodiments, R² is unsubstituted (C₁-C₃) alkyl. Inembodiments, R² is unsubstituted (C₁-C₂) alkyl. In embodiments, R² isR³³-substituted or unsubstituted (C₁-C₂) alkyl; R³³ is independentlyhalogen, —OH, —NH₂, —SH, substituted or unsubstituted (C₁-C₃) alkyl,substituted or unsubstituted 2 to 3 membered heteroalkyl, or substitutedor unsubstituted cyclopropyl. X³³ is independently halogen. Inembodiments, R² is unsubstituted methyl. In embodiments, R² isindependently hydrogen. In embodiments, R² is R³³-substituted orunsubstituted 2 to 5 membered heteroalkyl. In embodiments, R² isR³³-substituted or unsubstituted 3 membered heteroalkyl. In embodiments,R¹ is R³³-substituted or unsubstituted 2 to 5 membered heteroalkyl. Inembodiments, R² is 9-ethyl-9H-fluorene. In embodiments, R² is9-fluoromethoxycarbonyl. In embodiments, R² is

In embodiments, R³³ is independently oxo,

halogen, —CX³³ ₃, —CHX³⁰ ₂, —OCH₂X³³, —OCHX³³ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³³ ₃, —OCHX³³ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl. X³³ is independently halogen.In embodiments, R³³ is —Cl. In embodiments, R³³ is —OH.

In embodiments, R³³ is independently oxo,

halogen, —CX³³ ₃, —CHX³³ ₂, —OCH₂X³³, —OCHX³³ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHOH, —OCX³³ ₃, —OCHX³³ ₂,substituted or unsubstituted (C₁-C₃) alkyl, substituted or unsubstituted2 to 3 membered heteroalkyl, or substituted or unsubstitutedcyclopropyl; and X³³ is independently halogen. heterocycloalkyl. Inembodiments, R³³ is independently oxo,halogen, —CX³³ ₃, —CHX³³ ₂, —OCH₂X³³, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³³ ₃, —OCHX³³ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X³³ is independentlyhalogen. In embodiments, R³³ is unsubstituted cyclopropyl. Inembodiments, R³³ is unsubstituted cyclobutyl. In embodiments, R³³ isunsubstituted cyclopentyl. In embodiments, R³³ is unsubstitutedcyclohexyl. In embodiments, R³³ is substituted or unsubstituted phenyl.In embodiments, R³³ is unsubstituted phenyl. In embodiments, R³³ isunsubstituted benzyl.

In embodiments, R³³ is independently oxo,

halogen, —CX³³ ₃, —CHX³³ ₂, —OCH₂X³³, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³³ ₃, —OCHX³³ ₂,substituted or unsubstituted (C₁-C₃) alkyl, or substituted orunsubstituted 2 to 3 membered heteroalkyl; and X³³ is independentlyhalogen. In embodiments, R³³ is independently oxo,halogen, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, substituted orunsubstituted (C₁-C₃) alkyl, or substituted or unsubstituted 2 to 3membered heteroalkyl; and X³³ is independently halogen.

In embodiments, L¹ and R¹ are joined to form a substituted orunsubstituted 4 to 8 membered heterocycloalkyl. In embodiments, L¹ andR¹ are joined to form a R³⁰-substituted or unsubstituted 4 to 8 memberedheterocycloalkyl. In embodiments, L¹ and R² are joined to form asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl. Inembodiments, L¹ and R² are joined to form a R³³-substituted orunsubstituted 4 to 8 membered heterocycloalkyl.

In embodiments, R¹ and R² are joined to form a substituted orunsubstituted 3 to 6 membered heterocycloalkyl or substituted orunsubstituted 5 to 6 membered heteroaryl. In embodiments, R¹ and R² arejoined to form a substituted or unsubstituted 3 to 6 memberedheterocycloalkyl. In embodiments, R¹ and R² are joined to form aR³⁰-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R¹ and R² are joined to form a R³⁰-substituted orunsubstituted 5 membered heterocycloalkyl.

In embodiments, R⁵ is substituted or unsubstituted (C₁-C₅) alkyl orsubstituted or unsubstituted 2 to 5 membered heteroalkyl. Inembodiments, R⁵ is substituted or unsubstituted (C₁-C₅) alkyl. Inembodiments, R⁵ is unsubstituted (C₁-C₅) alkyl. In embodiments, R⁵ isunsubstituted (C₁-C₃) alkyl. In embodiments, R⁵ is unsubstituted methyl.In embodiments, R⁵ is hydrogen. In embodiments, R⁵ is propenyl. Inembodiments, R⁵ is ethenyl.

In embodiments, W is O. In embodiments, W is S.

In embodiments, L³ is —N(R⁶)—. In embodiments, L³ is —CH(R⁶)—. Inembodiments, L³ is a bond. In embodiments, L³ is —O—. In embodiments, L³is —CH₂—. In embodiments, L³ is —NH—.

In embodiments, R⁶ is hydrogen. In embodiments, R⁶ is substituted orunsubstituted (C₁-C₅) alkyl or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R⁶ is substituted or unsubstituted(C₁-C₅) alkyl. In embodiments, R⁶ is unsubstituted (C₁-C₅) alkyl. Inembodiments, R⁶ is unsubstituted (C₁-C₃) alkyl. In embodiments, R⁶ isunsubstituted methyl.

In embodiments, R⁶ is independently hydrogen, oxo,

halogen, —CX⁶³, —CHX⁶², —OCH₂X⁶, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁶³, —OCHX⁶²,R⁴⁵-substituted or unsubstituted alkyl, R⁴⁵-substituted or unsubstitutedheteroalkyl, R⁴⁵-substituted or unsubstituted cycloalkyl,R⁴⁵-substituted or unsubstituted heterocycloalkyl, R⁴⁵-substituted orunsubstituted aryl, or R⁴⁵-substituted or unsubstituted heteroaryl. X⁶is independently halogen. In embodiments, X⁶ is independently F or Cl.

R⁴⁵ is independently oxo,

halogen, —CX⁴⁵ ₃, —CHX⁴⁵ ₂, —OCH₂X⁴⁵, —OCHX⁴⁵ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCX⁴⁵ ₃, —OCHX⁴⁵ ₂, R⁴⁶-substituted or unsubstituted alkyl,R⁴⁶-substituted or unsubstituted heteroalkyl, R⁴⁶-substituted orunsubstituted cycloalkyl, R⁴⁶-substituted or unsubstitutedheterocycloalkyl, R⁴⁶-substituted or unsubstituted aryl, orR⁴⁶-substituted or unsubstituted heteroaryl. X⁴⁵ is independentlyhalogen. In embodiments, X⁴⁵ is independently F or Cl.R⁴⁶ is independently oxo,halogen, —CX⁴⁶ ₃, —CHX⁴⁶ ₂, —OCH₂X⁴⁶, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁴⁶ ₃, —OCHX⁴⁶ ₂,R⁴⁷-substituted or unsubstituted alkyl, R⁴⁷-substituted or unsubstitutedheteroalkyl, R⁴⁷-substituted or unsubstituted cycloalkyl,R⁴⁷-substituted or unsubstituted heterocycloalkyl, R⁴⁷-substituted orunsubstituted aryl, or R⁴⁷-substituted or unsubstituted heteroaryl. X⁴⁶is independently halogen. In embodiments, X⁴⁶ is independently F or Cl.

In embodiments, L² is a bond. In embodiments, L² is substituted orunsubstituted 2 to 5 membered heteroalkylene. In embodiments, L² isunsubstituted 2 to 5 membered heteroalkylene. In embodiments, L² issubstituted or unsubstituted (C₁-C₅) alkylene. In embodiments, L² issubstituted or unsubstituted (C₂-C₅) alkylene. In embodiments, L² isunsubstituted (C₁-C₅) alkylene. In embodiments, L² is unsubstituted(C₁-C₄) alkylene. In embodiments, L² is unsubstituted (C₁-C₃) alkylene.In embodiments, L² is unsubstituted (C₁-C₂) alkylene. In embodiments, L²is unsubstituted C₂ alkylene.

Each X may independently be —F. Each X may independently be —Cl. Each Xmay independently be —Br. Each X may independently be —I. Each X^(a) mayindependently be —F. Each X^(a) may independently be —Cl. Each X^(a) mayindependently be —Br. Each X^(a) may independently be —I.

Each n1 may independently be 0. Each n1 may independently be 1. Each n1may independently be 2. Each n1 may independently be 3. Each n1 mayindependently be 4. Each n may independently be 0. Each n mayindependently be 1. Each n may independently be 2. Each n mayindependently be 3. Each n may independently be 4. Each v1 mayindependently be 0. Each v1 may independently be 1. Each v1 mayindependently be 2. Each v1 may independently be 3. Each v1 mayindependently be 4. Each v may independently be 0. Each v mayindependently be 1. Each v may independently be 2. Each v mayindependently be 3. Each v2 may independently be 4. Each m1 mayindependently be 1. Each m1 may independently be 2. Each m mayindependently be 1. Each m may independently be 2.

In embodiments, the compound has the formula:

wherein R¹, R², R^(3A), R^(3B), R^(3C), R⁵, L¹, L², L³, W, and Ring Bare as described herein (e.g., including in formula I, II, and III, andembodiments thereof). In embodiments, the compound has the formula:

wherein R¹, R², R^(3A), R^(3B), R^(3C), R⁵, L¹, L², L³, W, and Ring Bare as described herein (e.g., including in formula I, II, and III, andembodiments thereof). In embodiments, the compound has the formula:

wherein R¹, R², R^(3A), R^(3B), R^(3C), R⁵, L¹, L², L³, W, and Ring Bare as described herein (e.g., including in formula I, II, and III, andembodiments thereof).

In embodiments, R^(3A), R^(3B), and R^(3C) are independently hydrogen,halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3A) is not hydrogen. Inembodiments, R^(3B) is not hydrogen. In embodiments, R^(3C) is nothydrogen. In embodiments, R^(3D) is not hydrogen. In embodiments, R^(3E)is not hydrogen. In embodiments, R^(3A)R^(3B), R^(3C), R^(3D), R^(3E)are each independently not halogen.

In embodiments, R^(3B) and R^(3C) are independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl and R^(3A) is independently halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl,or substituted or unsubstituted 2 to 5 membered heteroalkyl.

In embodiments, the compound has the formula:

wherein R^(3D), R^(3E), R⁵, L¹, L², and Ring B are as described herein.

In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁵, L¹, L², L³, W, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb andembodiments).

In embodiments, R³ is halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃,—OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl. In embodiments, R³ is —OH. Inembodiments, R³ is not hydrogen.

In embodiments, the compound has the formula:

wherein R¹, R², R^(3A), R^(3B), R^(3C), R^(3D), R^(3E), R⁵, L¹, L², L³,W, and Ring B are as described herein (e.g., including in formula I, II,III, IV, IVa, IVb and V, and embodiments thereof).

In embodiments, R^(3A), R^(3B), and R^(3C) are independently hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl. In embodiments, R^(3B) and R^(3C) areindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃,—OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl and R^(3A) is independentlyhalogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.

In embodiments, R^(3D) is hydrogen,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.

In embodiments, R^(3E) is hydrogen

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.

In embodiments, R^(3D) and R^(3E) are independently unsubstituted(C₁-C₅) alkyl. In embodiments, R^(3D) and R^(3E) are independentlyunsubstituted (C₁-C₃) alkyl. In embodiments, R^(3D) and R^(3E) areindependently unsubstituted (C₁-C₂) alkyl. In embodiments, R^(3D) andR^(3E) are independently unsubstituted methyl.

In embodiments, the compound has the formula:

wherein R¹, R², R^(3A), R^(3D), R^(3E), R⁵, L¹, L², L³, W, and Ring Bare as described herein (e.g., including in formula I, II, III, IV, IVa,IVb V, and VI, and embodiments thereof).

In embodiments, R^(3A) is —OH. In embodiments, Ring A is unsubstitutedphenyl.

In embodiments, the compound has the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, andVII, and embodiments thereof) and wherein d is an integer between 0 and3. In embodiments, the compound has the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, andVII, and embodiments thereof).

In embodiments, the compound has the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, andVII, and embodiments thereof) and wherein d is an integer between 0 and3.

In embodiments, the compound has the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,and VIII, and embodiments thereof) and wherein d is an integer between 0and 3.

In embodiments, the compound has the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, and IX, and embodiments thereof) and wherein d is an integerbetween 0 and 3.

In embodiments, the compound has the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, and X, and embodiments thereof) and wherein d is an integerbetween 0 and 3.

In embodiments, the compound has the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, and XI, and embodiments thereof) and wherein d is aninteger between 0 and 3.

In embodiments, the compound has the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, and XII, and embodiments thereof) and wherein d is aninteger between 0 and 3.

In embodiments, the compound has the formula:

wherein R¹, R², R³, L¹, and Ring B are as described herein (e.g.,including in formula I, II, III, IV, IVa, IVb V, VI, VII, VIII, IX, X,XI, XII, and XIII, and embodiments thereof).

In embodiments, Ring B is a substituted or unsubstituted phenyl orsubstituted or unsubstituted 5 to 6 membered heteroaryl; R³ is halogen,—OH, or —NH₂; R^(99a) is substituted or unsubstituted (C₁-C₃) alkyl; andR^(99b) is hydrogen or substituted or unsubstituted (C₁-C₃) alkyl. Inembodiments, Ring B is an unsubstituted phenyl. In embodiments, Ring Bis an unsubstituted 5 to 6 membered heteroaryl. In embodiments, Ring Bis an unsubstituted 3-thienyl. In embodiments, R³ is —OH. Inembodiments, R^(99a) is unsubstituted methyl. In embodiments, R^(99b) ishydrogen. In embodiments, R^(99b) is unsubstituted methyl. Inembodiments, R¹ and R² are unsubstituted methyl.

In embodiments, the compound has the formula:

wherein R¹, R², R³, L¹, R^(99a), R^(99b), and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII) and embodiments).

In embodiments, the compound has the formula:

wherein R¹, R², R³, L¹, R^(99a), R^(99b) and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII) and embodiments).

In embodiments, the compound has the formula:

wherein R¹, R², R³, L¹, R^(99a), R^(99b), and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII) and embodiments).

In embodiments, the compound has the formula:

wherein R¹, R², R³, L¹, R^(99a), R^(99b), and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII) and embodiments).

In embodiments, the compound has the formula:

wherein R¹, R², R^(3A), R^(3D), R^(3E), L¹, R^(99a), R^(99b), and Ring Bare as described herein (e.g., including in formula I, II, III, IV, IVa,IVb V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII,XIX, XX, and XXI) and embodiments).

In embodiments, Ring B is a substituted or unsubstituted phenyl orsubstituted or unsubstituted 5 to 6 membered heteroaryl; R^(3A) ishalogen, —OH, or —NH₂; R^(3D) is unsubstituted (C₁-C₂) alkyl; R^(3E) isunsubstituted (C₁-C₂) alkyl; R^(99a) is hydrogen or substituted orunsubstituted (C₁-C₃) alkyl; R^(99b) is substituted or unsubstituted(C₁-C₃) alkyl. In embodiments, Ring B is an unsubstituted phenyl. Inembodiments, Ring B is an unsubstituted 5 to 6 membered heteroaryl. Inembodiments, Ring B is an unsubstituted 3-thienyl. In embodiments,R^(3A) is —OH. In embodiments, R^(99b) is unsubstituted methyl. Inembodiments, R^(99a) is hydrogen. In embodiments, R^(99a) isunsubstituted methyl. In embodiments, R¹ and R² are unsubstitutedmethyl. In embodiments, R^(3D) is unsubstituted methyl. In embodiments,R^(3E) is unsubstituted methyl.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula: N

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

where n is 2. In embodiments, the compound has the formula:

In embodiments the compound has the formula:

where n is 3. In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

where n is 5. In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments. In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

R³², R³⁵, R³⁸, R^(38A), R^(38B), R^(38C), R^(38D), R^(38E), R⁴¹, R⁴⁴,R⁴⁷, R⁵⁰, R⁵³, R⁵⁶, R⁵⁹, R⁶², R⁶⁵, R⁶⁸, R⁷¹, R⁹⁸, and Riot areindependently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

In some embodiments, the compound is any one of the compounds describedherein (e.g., in an aspect, embodiment, claim, figure, table, orexample).

In some embodiments, a compound as described herein may include multipleinstances of R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, X^(a), X, m1, n1, v1,m, n, v, R³, R⁴, and/or other variables. In such embodiments, eachvariable may optional be different and be appropriately labeled todistinguish each group for greater clarity. For example, where each R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, X^(a), X, m1, n1, v1, m, n, v, R³,and/or R⁴, is different, they may be referred to, for example, asR^(7.1), R^(7.2), R^(7.3), R^(7.4), R^(7.5), R^(7.6), R^(7.7), R^(7.8),R^(7.9), R^(7.10), R^(7.11), R^(7.12), R^(7.13), R^(7.14), R^(7.15),R^(7.16), R^(7.17), R^(7.18), R^(7.19), R^(7.20), R^(7.21), R^(7.22),R^(7.23), R^(7.24), R^(7.25), R^(7.26), R^(7.27), R^(7.28), R^(7.29),R^(7.30), R^(7.31), R^(7.32), R^(7.33), R^(7.34), R^(7.35), R^(7.36),R^(7.37), R^(7.38), R^(7.39), R^(7.40), R^(7.41), R^(7.42), R^(8.1),R^(8.2), R^(8.3), R^(8.4), R^(8.5), R^(8.6), R^(8.7), R^(8.8), R^(8.9),R^(8.10), R^(8.11), R^(8.12), R^(8.13), R^(8.14), R^(8.15), R^(8.16),R^(8.17), R^(8.18), R^(8.19), R^(8.20), R^(8.21), R^(8.22), R^(8.23),R^(8.24), R^(8.25), R^(8.26), R^(8.27), R^(8.28), R^(8.29), R^(8.30),R^(8.31), R^(8.32), R^(8.33), R^(8.34), R^(8.35), R^(8.36), R^(8.37),R^(8.38), R^(8.39), R^(8.40), R^(8.41), R^(8.42), R^(9.1), R^(9.2),R^(9.3), R^(9.4), R^(9.5), R^(9.6), R^(9.7), R^(9.8), R^(9.9), R^(9.10),R^(9.11), R^(9.12), R^(9.13), R^(9.14), R^(9.15), R^(9.16), R^(9.17),R^(9.18), R^(9.19), R^(9.20), R^(9.21), R^(9.22), R^(9.23), R^(9.24),R^(9.25), R^(9.26), R^(9.27), R^(9.28), R^(9.29), R^(9.30), R^(9.31),R^(9.32), R^(9.33), R^(9.34), R^(9.35), R^(9.36), R^(9.37), R^(9.38),R^(9.39), R^(9.40), R^(9.41), R^(9.42), R^(10.1), R^(10.2), R^(10.3),R^(10.14), R^(10.5), R^(10.6), R^(10.7), R^(10.8), R^(10.9), R^(10.10),R^(10.11), R^(10.12), R^(10.13), R^(10.14), R^(10.15), R^(10.16),R^(10.17), R^(10.18), R^(10.19), R^(10.20), R^(10.21), R^(10.22),R^(10.23), R^(10.24), R^(10.25), R^(10.26), R^(10.27), R^(10.28),R^(10.29), R^(10.30), R^(10.31), R^(10.32), R^(10.33), R^(10.34),R^(10.35), R^(10.36), R^(10.37), R^(10.38), R^(10.39), R^(10.40),R^(10.41), R^(10.42), R^(11.1), R^(11.2), R^(11.3), R^(11.4), R^(11.5),R^(11.6), R^(11.7), R^(11.8), R^(11.9), R^(11.10), R^(11.11), R^(11.12),R^(11.13), R^(11.14), R^(11.15), R^(11.16), R^(11.17), R^(11.18),R^(11.19), R^(11.20), R^(11.21), R^(11.22), R^(11.23), R^(11.24),R^(11.25), R^(11.26), R^(11.27), R^(11.28), R^(11.29), R^(11.30),R^(11.31), R^(11.32), R^(11.33), R^(11.34), R^(11.35), R^(11.36),R^(11.37), R^(11.38), R^(11.39), R^(11.40), R^(11.41), R^(11.42),R^(12.1), R^(12.2), R^(12.3), R^(12.4), R^(12.5), R^(12.6), R^(12.7),R^(12.8), R^(12.9), R^(12.10), R^(12.11), R^(12.12), R^(12.13),R^(12.14), R^(12.15), R^(12.16), R^(12.17), R^(12.18), R^(12.19),R^(12.20), R^(12.21), R^(12.22), R^(12.23), R^(12.24), R^(12.25),R^(12.26), R^(12.27), R^(12.28), R^(12.29), R^(12.30), R^(12.31),R^(12.32), R^(12.33), R^(12.34), R^(12.35), R^(12.36), R^(12.37),R^(12.38), R^(12.39), R^(12.40), R^(12.41), R^(12.42), R^(13.1),R^(13.2), R^(13.3), R^(13.4), R^(13.5), R^(13.6), R^(13.7), R^(13.8),R^(13.9), R^(13.10), R^(13.11), R^(13.12), R^(13.13), R^(13.14),R^(13.15), R^(13.16), R^(13.17), R^(13.18), R^(13.19), R^(13.20),R^(13.21), R^(13.22), R^(13.23), R^(13.24), R^(13.25), R^(13.26),R^(13.27), R^(13.28), R^(13.29), R^(13.30), R^(13.31), R^(13.32),R^(13.33), R^(13.34), R^(13.35), R^(13.36), R^(13.37), R^(13.38),R^(13.39), R^(13.40), R^(13.41), R^(13.42), R^(14.1), R^(14.2),R^(14.3), R^(14.4), R^(14.5), R^(14.6), R^(14.7), R^(14.8), R^(14.9),R^(14.10), R^(14.11), R^(14.12), R^(14.13), R^(14.14), R^(14.15),R^(14.16), R^(14.17), R^(14.18), R^(14.19), R^(14.20), R^(14.21),R^(14.22), R^(14.23), R^(14.24), R^(14.25), R^(14.26), R^(14.27),R^(14.28), R^(14.29), R^(14.30), R^(14.31), R^(14.32), R^(14.33),R^(14.34), R^(14.35), R^(14.36), R^(14.37), R^(14.38), R^(14.39),R^(14.40), R^(14.41), R^(14.42), X^(a1), X^(a2), X^(a3), X^(a4), X^(a5),X^(a6), X^(a7), X^(a8), X^(a9), X^(a10), X^(a11), X^(a12), X^(a13),X^(a14), X^(a15), X^(a16), X^(a17), X^(a18), X^(a19), X^(a20), X^(a21),X^(a22), X^(a23), X^(a24), X^(a25), X^(a26), X^(a27), X^(a28), X^(a29),X^(a30), X^(a31), X^(a32), X^(a33), X^(a34), X^(a35), X^(a36), X^(a37),X^(a38), X^(a39), X^(a40), X^(a41), X^(a42), X-¹, X-², X-³, X-⁴, X-⁵,X-⁶, X-⁷, X-⁸, X- ⁹, X¹⁰, X¹¹, X-¹², X-¹³, X-¹⁴, X-¹⁵, X-¹⁶, X-¹⁷, X-¹⁸,X-¹⁹, X-²⁰, X-²¹, X-²², X-²³, X-²⁴, X-²⁵, X-²⁶, X-²⁷, X-²⁸, X-²⁹, X-³⁰,X-³¹, X-³², X-³³, X-³⁴, X-³⁵, X-³⁶, X-³⁷, X-³⁸, X-³⁹, X-⁴⁰, X-⁴¹, X-⁴²,m1¹, m1², m1³, m1⁴, m1⁵, m¹, m², m³, m⁴, m⁵, n1¹, n1², n1³, n1⁴, n1⁵,n¹, n², n³, n⁴, n⁵, v1¹, v1², v1³, v1⁴, V1⁵, v¹, v², v³, v⁴, v⁵,R^(3.1), R^(3.2), R^(3.3), R^(3.4), R^(3.5), R^(3.6), R^(3.7), R^(3.8),R^(3.9), R^(3.10), R^(3.11), R^(3.12), R^(3.13), R^(3.14), R^(3.15),R^(3.16), R^(3.17), R^(3.18), R^(3.19), R^(3.20), R^(3.21), R^(3.22),R^(3.23), R^(3.24), R^(3.25), R^(3.26), R^(3.27), R^(3.28), R^(3.29),R^(3.30), R^(3.31), R^(3.32), R^(3.33), R^(3.34), R^(3.35), R^(3.36),R^(3.37), R^(3.38), R^(3.39), R^(3.40), R^(3.41), R^(3.42), R^(4.1),R^(4.2), R^(4.3), R^(4.4), R^(4.5), R^(4.6), R^(4.7), R^(4.8), R^(4.9),R^(4.10), R^(4.11), R^(4.12), R^(4.13), R^(4.14), R^(4.15), R^(4.16),R^(4.17), R^(4.18), R^(4.19), R^(4.20), R^(4.21), R^(4.22), R^(4.23),R^(4.24), R^(4.25), R^(4.26), R^(4.27), R^(4.28), R^(4.29), R^(4.30),R^(4.31), R^(4.32), R^(4.33), R^(4.34), R^(4.35), R^(4.36), R^(4.37),R^(4.38), R^(4.39), R^(4.40), R^(4.41), R^(4.42), respectively, whereinthe definition of R⁷ is assumed by R^(7.1), R^(7.2), R^(7.3), R^(7.4),R^(7.5), R^(7.6), R^(7.7), R^(7.8), R^(7.9), R^(7.10), R^(7.11),R^(7.12), R^(7.13), R^(7.14), R^(7.15), R^(7.16), R^(7.17), R^(7.18),R^(7.19), R^(7.20), R^(7.21), R^(7.22), R^(7.23), R^(7.24), R^(7.25),R^(7.26), R^(7.27), R^(7.28), R^(7.29), R^(7.30), R^(7.31), R^(7.32),R^(7.33), R^(7.34), R^(7.35), R^(7.36), R^(7.37), R^(7.38), R^(7.39),R^(7.40), R^(7.41), R^(7.42); R⁸ is assumed by R^(8.1), R^(8.2),R^(8.3), R^(8.4), R⁸⁵, R^(8.6), R^(8.7), R^(8.8), R^(8.9), R^(8.10),R^(8.11), R^(8.12), R^(8.13), R^(8.14), R^(8.15), R^(8.16), R^(8.17),R^(8.18), R^(8.19), R^(8.20), R^(8.21), R^(8.22), R^(8.23), R^(8.24),R^(8.25), R^(8.26), R^(8.27), R^(8.28), R^(8.29), R^(8.30), R^(8.31),R^(8.32), R^(8.33), R^(8.34), R^(8.35), R^(8.36), R^(8.37), R^(8.38),R^(8.39), R^(8.40), R^(8.41), R^(8.42); R⁹ is assumed by R^(9.1),R^(9.2), R^(9.3), R^(9.4), R⁹⁵, R^(9.6), R^(9.7), R^(9.8), R^(9.9),R^(9.10), R^(9.11), R^(9.12), R^(9.13), R^(9.14), R^(9.15), R^(9.16),R^(9.17), R^(9.18), R^(9.19), R^(9.20), R^(9.21), R^(9.22), R^(9.23),R^(9.24), R^(9.25), R^(9.26), R^(9.27), R^(9.28), R^(9.29), R^(9.30),R^(9.31), R^(9.32), R^(9.33), R^(9.34), R^(9.35), R^(9.36), R^(9.37),R^(9.38), R^(9.39), R^(9.40), R^(9.41), R^(9.42); R¹⁰ is assumed byR^(10.1), R^(10.2), R^(10.4), R^(10.5), R^(10.6), R^(11.7), R^(10.8),R^(10.9), R^(10.10), R^(10.11), R^(10.12), R^(10.13), R^(10.14),R^(10.15), R^(10.16), R^(10.17), R^(10.18), R^(10.19), R^(10.20),R^(10.21), R^(10.22), R^(10.23), R^(10.24), R^(10.25), R^(10.26),R^(10.27), R^(10.28), R^(10.29), R^(10.30), R^(10.31), R^(10.32),R^(10.33), R^(10.34), R^(10.35), R^(10.36), R^(10.37), R^(10.38),R^(10.39), R^(10.40), R^(10.41), R^(10.42); R¹¹ is assumed by R^(11.1),R^(11.2), R^(11.3), R^(11.4), R^(11.5), R^(11.6), R^(11.7), R¹¹⁸,R^(11.9), R^(1.10), R^(1.11), R^(11.12), R^(11.13), R^(11.14),R^(11.15), R^(11.16), R^(11.17), R^(11.18), R^(11.19), R^(11.20),R^(11.21), R^(11.22), R^(11.23), R^(11.24), R^(11.25), R^(11.26),R^(11.27), R^(11.28), R^(11.29), R^(11.30), R^(11.31), R^(11.32),R^(11.33), R^(11.34), R^(11.35), R^(11.36), R^(11.37), R^(11.38),R^(11.39), R^(11.40), R^(11.41), R^(11.42); R¹² is assumed by R^(12.1),R^(12.2), R^(12.3), R^(12.4), R¹²⁵, R^(12.6), R^(12.7), R^(12.8),R^(12.9), R^(12.10), R^(12.11), R^(12.12), R^(12.13), R^(12.14),R^(12.15), R^(12.16), R^(12.17), R^(12.18), R^(12.19), R^(12.20),R^(12.21), R^(12.22), R^(12.23), R^(12.24), R^(12.25), R^(12.26),R^(12.27), R^(12.28), R^(12.29), R^(12.30), R^(12.31), R^(12.32),R^(12.33), R^(12.34), R^(12.35), R^(12.36), R^(12.37), R^(12.38),R^(12.39), R^(12.40), R^(12.41), R^(12.42); R¹³ is assumed by R^(13.1),R^(13.2), R^(13.3), R^(13.4), R^(13.5), R^(13.6), R^(13.7), R^(13.8),R^(13.9), R^(13.10), R^(13.11), R^(13.12), R^(13.13), R^(13.14),R^(13.15), R^(13.16), R^(13.17), R^(13.18), R^(13.19), R^(13.20),R^(13.21), R^(13.22), R^(13.23), R^(13.24), R^(13.25), R^(13.26),R^(13.27), R^(13.28), R^(13.29), R^(13.30), R^(13.31), R^(13.32),R^(13.33), R^(13.34), R^(13.35), R^(13.36), R^(13.37), R^(13.38),R^(13.39), R^(13.40), R^(13.41), R^(13.42); R¹⁴ is assumed by R^(14.1),R^(14.2), R^(14.3), R^(14.4), R^(14.5), R^(14.6), R^(14.7), R^(14.8),R^(14.9), R^(14.10), R^(14.11), R^(14.12), R^(14.13), R^(14.14),R^(14.15), R^(14.16), R^(14.17), R^(14.18), R^(14.19), R^(14.20),R^(14.21), R^(14.22), R^(14.23), R^(14.24), R^(14.25), R^(14.26),R^(14.27), R^(14.28), R^(14.29), R^(14.30), R^(14.31), R^(14.32),R^(14.33), R^(14.34), R^(14.35), R^(14.36), R^(14.37), R^(14.38),R^(14.39), R^(14.40), R^(14.41), R^(14.42); X^(a) is assumed by X^(a1),X^(a2), X^(a3), X^(a4), X^(a5), X^(a6), X^(a7), X^(a8), X^(a9), X^(a10),X^(a11), X^(a12,) X^(a13), X^(a14), X^(a15), X^(a16), X^(a17), X^(a18),X^(a19), X^(a20), X^(a21), X^(a22), X^(a23), X^(a24), X^(a25), X^(a26),X^(a27), X^(a28), X^(a29), X^(a30), X^(a31), X^(a32), X^(a33), X^(a34),X^(a35), X^(a36), X^(a37), X^(a38), X^(a39), X^(a40), X^(a41), X^(a42);X is assumed by X-¹, X-², X-³, X-⁴, X-⁵, X-⁶, X-⁷, X-⁸, X-⁹, X-¹⁰, X-¹¹,X-¹², X-¹³, X-¹⁴, X-¹⁵, X-¹⁶, X-¹⁷, X-¹⁸, X- ¹⁹, X-²⁰, X-²¹, X-²², X-²³,X-²⁴, X-²⁵, X-²⁶, X-²⁷, X-²⁸, X-²⁹, X-³⁰, X-³¹, X-³², X-³³, X-³⁴, X-³⁵,X-³⁶, X-³⁷, X-³⁸, X-³⁹, X-⁴⁰, X-⁴¹, X-⁴²; m1 is assumed by m1, m1², m1³,m1⁴, m1⁵; n1 is assumed by n1¹, n1², n1³, n1⁴, n1⁵; v1 is assumed byv1¹, v1², v1³, v1⁴, v1⁵; m is assumed by m¹, m², m³, m⁴, m⁵; n isassumed by n¹, n², n³, n⁴, n⁵; v is assumed by v¹, v², v³, v⁴, v⁵; R³ isassumed by R^(3.1), R^(3.2), R^(3.3), R^(3.4), R^(3.5), R^(3.6),R^(3.7), R^(3.8), R^(3.9), R^(3.10), R^(3.11), R^(3.12), R^(3.13),R^(3.14), R^(3.15), R^(3.16), R^(3.17), R^(3.18), R^(3.19), R^(3.20),R^(3.21), R^(3.22), R^(3.23), R^(3.24), R^(3.25), R^(3.26), R^(3.27),R^(3.28), R^(3.29), R^(3.30), R^(3.31), R^(3.32), R^(3.33), R^(3.34),R^(3.35), R^(3.36), R^(3.37), R^(3.38), R^(3.39), R^(3.40), R^(3.41),R^(3.42); and/or R⁴ is assumed by R^(4.1), R^(4.2), R^(4.3), R^(4.4),R^(4.5), R^(4.6), R^(4.7), R^(4.8), R^(4.9), R^(4.10), R^(4.11),R^(4.12), R^(4.13), R^(4.14), R^(4.15), R^(4.16), R^(4.17), R^(4.18),R^(4.19), R^(4.20), R^(4.21), R^(4.22), R^(4.23), R^(4.24), R^(4.25),R^(4.26), R^(4.27), R^(4.28), R^(4.29), R^(4.20), R^(4.31), R^(4.22),R^(4.23), R^(4.24), R^(4.25), R^(4.26), R^(4.27), R^(4.38), R^(4.39),R^(4.40), R^(4.41), R^(4.42) The variables used within a definition ofR⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, X^(a), X, m1, n1, v1, m, n, v, R³,R⁴, and/or other variables that appear at multiple instances and aredifferent may similarly be appropriately labeled to distinguish eachgroup for greater clarity. In some embodiments, the compound is acompound described herein (e.g., in an aspect, embodiment, example,claim, table, scheme, drawing, or figure).

In embodiments, the compound comprises a higher binding affinity for themu opioid receptor than for the kappa opioid receptor. In embodiments,the compound comprises a greater than 10-fold higher binding affinityfor the mu opioid receptor than for the kappa opioid receptor. Inembodiments, the compound comprises a greater than 100-fold higherbinding affinity for the mu opioid receptor than for the kappa opioidreceptor. In embodiments, the compound comprises a higher bindingaffinity for the mu opioid receptor than for the delta opioid receptor.In embodiments, the compound comprises a greater than 10-fold higherbinding affinity for the mu opioid receptor than for the delta opioidreceptor. In embodiments, the compound comprises a greater than 100-foldhigher binding affinity for the mu opioid receptor than for the deltaopioid receptor. In embodiments, the compound comprises a higher bindingaffinity for the mu opioid receptor than for the nociceptin receptor. Inembodiments, the compound comprises a greater than 10-fold higherbinding affinity for the mu opioid receptor than for the nociceptinreceptor. In embodiments, the compound comprises a greater than 100-foldhigher binding affinity for the mu opioid receptor than for thenociceptin receptor.

In embodiments, the compound comprises a greater than 10-fold, 20-fold,30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-fold higherbinding affinity for the mu opioid receptor than for the kappa opioidreceptor. In embodiments, the compound comprises a greater than 10-fold,20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or 1000-foldhigher binding affinity for the mu opioid receptor than for the deltaopioid receptor. In embodiments, the compound comprises a greater than10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 100-fold, 500-fold, or1000-fold higher binding affinity for the mu opioid receptor than forthe nociceptin receptor.

In embodiments, the compound comprises a lower addiction potential thanmedically used opioids. In embodiments, the compound comprises a loweraddiction potential than medically used opiates. In embodiments, thecompound comprises a lower addiction potential than morphine. Inembodiments, the compound comprises a lower addiction potential thanfentanyl. In embodiments, the compound comprises a lower addictionpotential than heroin. In embodiments, the compound comprises a loweraddiction potential than hydrocodone. In embodiments, the compoundcomprises a lower addiction potential than oxycodone. In embodiments,the compound comprises a lower addiction potential than morphinederivatives. In embodiments, the compound comprises a lower addictionpotential than medically used morphine derivatives. In embodiments, thecompound comprises a lower addiction potential than codeine. Inembodiments, the compound comprises a lower addiction potential thanmethadone. In embodiments, the compound comprises a lower addictionpotential than hydromorphone. In embodiments, the lowered addictionpotential of the compound compared to the opioid is 10-fold. Inembodiments, the lowered addiction potential of the compound compared tothe opioid is 100-fold. In embodiments, the lowered addiction potentialof the compound compared to the opioid is for an identical amount of thecompound and the opioid. In embodiments, the lowered addiction potentialof the compound compared to the opioid is for an identical level of painrelief.

In embodiments, unless otherwise indicated, a compound described hereinis a racemic mixture of all stereoisomers. In embodiments, unlessotherwise indicated, a compound described herein is a racemic mixture ofall enantiomers. In embodiments, unless otherwise indicated, a compounddescribed herein is a racemic mixture of two opposite stereoisomers. Inembodiments, unless otherwise indicated, a compound described herein isa racemic mixture of two opposite enantiomers. In embodiments, unlessotherwise indicated, a compound described herein is a singlestereoisomer. In embodiments, unless otherwise indicated, a compounddescribed herein is a single enantiomer.

In embodiments, the compound is not:

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In embodiments, the compound is not

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R^(3A), R^(3B), R^(3C), R⁵, L¹, L², L³, W, and Ring Bare as described herein (e.g., including in formula I, II, and III, andembodiments thereof). In embodiments, the compound is not a compoundwherein R^(3A) is hydrogen. In embodiments, the compound is not acompound wherein Ring B is substituted. In embodiments, the compound isnot a compound wherein Ring B is substituted aryl. In embodiments, thecompound is not a compound wherein Ring B is substituted heteroaryl. Inembodiments, the compound is not a compound wherein Ring B issubstituted thienyl. In embodiments, the compound is not a compoundwherein Ring B is substituted pyridyl. In embodiments, the compound isnot a compound wherein Ring B is substituted phenyl. In embodiments, thecompound is not a compound having the formula:

wherein R^(3A), R^(3B), and R^(3E) are independently not halogen.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R³, R⁵, L¹, L², L³, W, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb andembodiments). In embodiments, the compound is not a compound wherein R³is hydrogen. In embodiments, the compound is not a compound wherein RingB is substituted. In embodiments, the compound is not a compound whereinRing B is substituted aryl. In embodiments, the compound is not acompound wherein Ring B is substituted heteroaryl. In embodiments, thecompound is not a compound wherein Ring B is substituted thienyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted pyridyl. In embodiments, the compound is not a compoundwherein Ring B is substituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R^(3A), R^(3B), R^(3C), R^(3D), R^(3E), R⁵, L¹, L², L³,W, and Ring B are as described herein (e.g., including in formula I, II,III, IV, IVa, IVb and V, and embodiments thereof). In embodiments, thecompound is not a compound wherein R^(3A) is hydrogen. In embodiments,the compound is not a compound wherein Ring B is substituted. Inembodiments, the compound is not a compound wherein Ring B issubstituted aryl. In embodiments, the compound is not a compound whereinRing B is substituted heteroaryl. In embodiments, the compound is not acompound wherein Ring B is substituted thienyl. In embodiments, thecompound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R^(3A), R^(3D), R^(3E), R⁵, L¹, L², L³, W, and Ring Bare as described herein (e.g., including in formula I, II, III, IV, IVa,IVb V, and VI, and embodiments thereof). In embodiments, the compound isnot a compound wherein R^(3A) is hydrogen. In embodiments, the compoundis not a compound wherein Ring B is substituted. In embodiments, thecompound is not a compound wherein Ring B is substituted aryl. Inembodiments, the compound is not a compound wherein Ring B issubstituted heteroaryl. In embodiments, the compound is not a compoundwherein Ring B is substituted thienyl. In embodiments, the compound isnot a compound wherein Ring B is substituted pyridyl. In embodiments,the compound is not a compound wherein Ring B is substituted phenyl.

In embodiments, the compound is not a compound having the formula:

R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as described herein (e.g.,including in formula I, II, III, IV, IVa, IVb V, VI, and VII, andembodiments thereof) and wherein d is an integer between 0 and 3. Inembodiments, the compound is not a compound wherein Ring A isunsubstituted. In embodiments, the compound is not a compound whereinRing A is unsubstituted aryl. In embodiments, the compound is not acompound wherein Ring A is unsubstituted phenyl. In embodiments, thecompound is not a compound wherein Ring B is substituted. Inembodiments, the compound is not a compound wherein Ring B issubstituted aryl. In embodiments, the compound is not a compound whereinRing B is substituted heteroaryl. In embodiments, the compound is not acompound wherein Ring B is substituted thienyl. In embodiments, thecompound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,and VIII, and embodiments thereof) and wherein d is an integer between 0and 3. In embodiments, the compound is not a compound wherein Ring A isunsubstituted. In embodiments, the compound is not a compound whereinRing A is unsubstituted aryl. In embodiments, the compound is not acompound wherein Ring A is unsubstituted phenyl. In embodiments, thecompound is not a compound wherein Ring B is substituted. Inembodiments, the compound is not a compound wherein Ring B issubstituted aryl. In embodiments, the compound is not a compound whereinRing B is substituted heteroaryl. In embodiments, the compound is not acompound wherein Ring B is substituted thienyl. In embodiments, thecompound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, and IX, and embodiments thereof) and wherein d is an integerbetween 0 and 3. In embodiments, the compound is not a compound whereinRing A is unsubstituted. In embodiments, the compound is not a compoundwherein Ring A is unsubstituted aryl. In embodiments, the compound isnot a compound wherein Ring A is unsubstituted phenyl. In embodiments,the compound is not a compound wherein Ring B is substituted. Inembodiments, the compound is not a compound wherein Ring B issubstituted aryl. In embodiments, the compound is not a compound whereinRing B is substituted heteroaryl. In embodiments, the compound is not acompound wherein Ring B is substituted thienyl. In embodiments, thecompound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, and X, and embodiments thereof) and wherein d is an integerbetween 0 and 3. In embodiments, the compound is not a compound whereinRing A is unsubstituted. In embodiments, the compound is not a compoundwherein Ring A is unsubstituted aryl. In embodiments, the compound isnot a compound wherein Ring A is unsubstituted phenyl. In embodiments,the compound is not a compound wherein Ring B is substituted. Inembodiments, the compound is not a compound wherein Ring B issubstituted aryl. In embodiments, the compound is not a compound whereinRing B is substituted heteroaryl. In embodiments, the compound is not acompound wherein Ring B is substituted thienyl. In embodiments, thecompound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, and XI, and embodiments thereof) and wherein d is aninteger between 0 and 3. In embodiments, the compound is not a compoundwherein Ring A is unsubstituted. In embodiments, the compound is not acompound wherein Ring A is unsubstituted aryl. In embodiments, thecompound is not a compound wherein Ring A is unsubstituted phenyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted. In embodiments, the compound is not a compound wherein RingB is substituted aryl. In embodiments, the compound is not a compoundwherein Ring B is substituted heteroaryl. In embodiments, the compoundis not a compound wherein Ring B is substituted thienyl. In embodiments,the compound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R⁵, R⁶, L¹, W, Ring A, and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, and XII, and embodiments thereof) and wherein d is aninteger between 0 and 3. In embodiments, the compound is not a compoundwherein Ring A is unsubstituted. In embodiments, the compound is not acompound wherein Ring A is unsubstituted aryl. In embodiments, thecompound is not a compound wherein Ring A is unsubstituted phenyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted. In embodiments, the compound is not a compound wherein RingB is substituted aryl. In embodiments, the compound is not a compoundwherein Ring B is substituted heteroaryl. In embodiments, the compoundis not a compound wherein Ring B is substituted thienyl. In embodiments,the compound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R³, L¹, and Ring B are as described herein (e.g.,including in formula I, II, III, IV, IVa, IVb V, VI, VII, VIII, IX, X,XI, XII, and XIII, and embodiments thereof). In embodiments, thecompound is not a compound wherein R³ is hydrogen. In embodiments, thecompound is not a compound wherein R³ is independently halogen. Inembodiments, the compound is not a compound wherein Ring B issubstituted. In embodiments, the compound is not a compound wherein RingB is substituted aryl. In embodiments, the compound is not a compoundwherein Ring B is substituted heteroaryl. In embodiments, the compoundis not a compound wherein Ring B is substituted thienyl. In embodiments,the compound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R³, L¹, R^(99a), R^(99b), and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII) and embodiments). Inembodiments, the compound is not a compound wherein R³ is hydrogen. Inembodiments, the compound is not a compound wherein Ring B issubstituted. In embodiments, the compound is not a compound wherein RingB is substituted aryl. In embodiments, the compound is not a compoundwherein Ring B is substituted heteroaryl. In embodiments, the compoundis not a compound wherein Ring B is substituted thienyl. In embodiments,the compound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R³, L¹, R^(99a), R^(99b), and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII) and embodiments). Inembodiments, the compound is not a compound wherein R³ is hydrogen. Inembodiments, the compound is not a compound wherein Ring B issubstituted. In embodiments, the compound is not a compound wherein RingB is substituted aryl. In embodiments, the compound is not a compoundwherein Ring B is substituted heteroaryl. In embodiments, the compoundis not a compound wherein Ring B is substituted thienyl. In embodiments,the compound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R³, L¹, R^(99a), R^(99b), and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII) and embodiments). Inembodiments, the compound is not a compound wherein R³ is hydrogen. Inembodiments, the compound is not a compound wherein Ring B issubstituted. In embodiments, the compound is not a compound wherein RingB is substituted aryl. In embodiments, the compound is not a compoundwherein Ring B is substituted heteroaryl. In embodiments, the compoundis not a compound wherein Ring B is substituted thienyl. In embodiments,the compound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R³, L¹, R^(99a), R^(99b), and Ring B are as describedherein (e.g., including in formula I, II, III, IV, IVa, IVb V, VI, VII,VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, and XVII) and embodiments). Inembodiments, the compound is not a compound wherein R³ is hydrogen. Inembodiments, the compound is not a compound wherein Ring B issubstituted. In embodiments, the compound is not a compound wherein RingB is substituted aryl. In embodiments, the compound is not a compoundwherein Ring B is substituted heteroaryl. In embodiments, the compoundis not a compound wherein Ring B is substituted thienyl. In embodiments,the compound is not a compound wherein Ring B is substituted pyridyl. Inembodiments, the compound is not a compound wherein Ring B issubstituted phenyl.

In embodiments, the compound is not a compound having the formula:

wherein R¹, R², R^(3A), R^(3D), R^(3E), L¹, R^(99a), R^(99b), and Ring Bare as described herein (e.g., including in formula I, II, III, IV, IVa,IVb V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII,XIX, XX, and XXI) and embodiments). In embodiments, the compound is nota compound wherein R^(3A) is hydrogen. In embodiments, the compound isnot a compound wherein Ring B is substituted. In embodiments, thecompound is not a compound wherein Ring B is substituted aryl. Inembodiments, the compound is not a compound wherein Ring B issubstituted heteroaryl. In embodiments, the compound is not a compoundwherein Ring B is substituted thienyl. In embodiments, the compound isnot a compound wherein Ring B is substituted pyridyl. In embodiments,the compound is not a compound wherein Ring B is substituted phenyl.

In embodiments, the compound described herein is capable of crossing theblood brain barrier. In embodiments, the compound described herein is apartial agonist of the μOR. In embodiments, the compound describedherein is a partial agonist of the μOR. In embodiments, the compounddescribed herein is a partial antagonist of the μOR. Partial agonism isa common term of art, as described in Calvey et. al (Principles andPractice of Pharmacology for Anaesthetists p. 62 (2009)).

III. Pharmaceutical Compositions

In an aspect is provided a pharmaceutical composition including acompound described herein (including in embodiments, examples, figures,or tables) and a pharmaceutically acceptable excipient.

In embodiments, the pharmaceutical composition includes an effectiveamount of the compound. In embodiments, the pharmaceutical compositionincludes a therapeutically effective amount of the compound. Inembodiments, the pharmaceutical composition includes a second agent(e.g., an additional pain reliever, anti-fibrotic agent,anti-inflammatory agent).

The pharmaceutical compositions may include optical isomers,diastereomers, or pharmaceutically acceptable salts of the modulatorsdisclosed herein. The compound included in the pharmaceuticalcomposition may be covalently attached to a carrier moiety.Alternatively, the compound included in the pharmaceutical compositionis not covalently linked to a carrier moiety.

IV. Methods of Treatment

In an aspect is provided a method of treating pain in a subject in needof the treatment, the method including administering an effective amountof a compound described herein (including in embodiments, examples,figures, or tables). An appropriate or effective amount is an amountsufficient to provide the desired therapeutic effect (e.g., treat oralleviate pain or treat or reduce inflammation). Compounds of theinvention may be used in combination with other compounds of theinvention or with other drugs that may also be useful in the treatment,prevention, or the suppression of pain. In embodiments, the pain isassociated with pulmonary edema, kidney stones, minor injuries, woundhealing, skin wound healing, vaginitis, candidiasis, lumbarspondylanhrosis, lumbar spondylarthrosis, vascular diseases, migraineheadaches, sinus headaches, tension headaches, dental pain,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, type II diabetes,myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome,Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swellingoccurring after injury, or myocardial ischemia, or osteoarthritis. Inembodiments, the pain is post surgical pain. In embodiments, thecompounds described herein are used to treat moderate or severe acutepain. In embodiments, the pain is paroxysmal spontaneous pain, steadypain, allodynia associated with postherpetic neuralgia. In embodiments,the pain is cancer-related pain.

In embodiments, the pain is associated with invasive procedures (e.g.,lumbar puncture, biopsy, surgical intervention). In embodiments, thepain is associated with mechanical or metabolic injury to the nervoussystem, tumor infiltration of nerves or nerve roots, or exposure tochemotherapeutic agents or radiation therapy.

In embodiments, the pain is acute pain (e.g., post surgical pain). Inembodiments, the pain is chronic pain. In embodiments, chronic pain ispain that has persisted for at least 1 month. In embodiments, chronicpain is pain that has persisted for at least 2 months. In embodiments,chronic pain is pain that has persisted for at least 3 months. Inembodiments, chronic pain is pain that has persisted for at least 4months. In embodiments, chronic pain is pain that has persisted for atleast 5 months. In embodiments, chronic pain is pain that has persistedfor at least 6 months. In embodiments, the method does not include anincreased risk of respiratory depression. In embodiments, the methoddoes not include respiratory depression. In embodiments, the method doesnot include an increased risk of constipation. In embodiments, themethod does not include constipation. In embodiments, the pain isaffective pain. Affective pain may be assessed using an objectivepsychophysiological measure, subjective ratings, (e.g., the eye-blinkcomponent of the startle reflex), or methods described herein (e.g.,Example 3). In embodiments, an increased risk indicates an elevatedprobability of experiencing a symptom (e.g., constipation, respiratorydepression). In embodiments, an increased risk is 1%, 2%, 3%, 4%, 5%,10%, 15%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%,400%, 500%, or 1000%. In embodiments, an increased risk is about 1%, 2%,3%, 4%, 5%, 10%, 15%, 25%, 30%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 100%,200%, 300%, 400%, 500%, or about 1000%.

In an aspect is provided a method of treating opioid overdose in asubject in need of the treatment, the method including administering aneffective amount of a compound described herein (including inembodiments, examples, figures, or tables).

In an aspect is provided a method of treating addiction in a subject inneed of the treatment, the method including administering an effectiveamount compound described herein (including in embodiments, examples,figures, or tables).

In embodiments, the addiction is opioid addiction. In embodiments, theaddiction is heroin addiction. In embodiments, the addiction isoxycodone addiction. In embodiments, the addiction is morphineaddiction. In embodiments, the addiction is fentanyl addiction. Inembodiments, the addiction is codeine addiction. In embodiments, theaddiction is nicotine addiction. In embodiments, the method does notinclude an increased risk of respiratory depression. In embodiments, themethod does not include respiratory depression. In embodiments, themethod does not include an increased risk of constipation. Inembodiments, the method does not include constipation.

In an aspect is provided a method of treating a psychiatric disorder ina subject in need of the treatment, the method including administeringan effective amount of a compound described herein (including inembodiments, examples, figures, or tables).

In embodiments, the psychiatric disorder is depression. In embodiments,the psychiatric disorder is anxiety. In embodiments, the method does notinclude an increased risk of respiratory depression. In embodiments, themethod does not include respiratory depression. In embodiments, themethod does not include an increased risk of constipation. Inembodiments, the method does not include constipation.

In an aspect is provided a method of treating drug poisoning in asubject in need of the treatment, the method including administering aneffective amount of a compound described herein (including inembodiments, examples, figures, or tables).

In embodiments, the drug is an opioid. In embodiments, the drug is anopiate. In embodiments, the drug is heroin. In embodiments, the drug isfentanyl. In embodiments, the drug is morphine. In embodiments, the drugis oxycodone.

The compounds of the invention (i.e. compounds described herein,including in embodiments, examples, figures, tables) can be administeredalone or can be coadministered to the patient. Coadministration is meantto include simultaneous or sequential administration of the compoundsindividually or in combination (more than one compound). Thus, thepreparations can also be combined, when desired, with other activesubstances (e.g. to reduce metabolic degradation or anti-cancer agents).

V. Methods of Modulating Activity

In an aspect is provided a method of modulating the activity of anopioid receptor protein, the method including contacting the opioidreceptor protein with an effective amount of a compound described herein(including in embodiments, examples, figures, or tables).

In embodiments, modulating is activating. In embodiments, activatingincludes a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% orgreater as compared to a control level. In embodiments, modulating isinhibiting. In embodiments, inhibiting includes a change of 10%, 20%,30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a controllevel can include complete elimination.

In embodiments, the opioid receptor is a human mu opioid receptor.

In embodiments, the method does not include modulating arrestinfunction. In embodiments, the method does not include increasingarrestin function. In embodiments, the method does not includeactivating arrestin. In embodiments, the method does not includemodulating the activity of a human kappa opioid receptor. Inembodiments, the method does not include modulating the activity of ahuman delta opioid receptor. In embodiments, the method does not includemodulating the activity of a human nociceptin receptor.

In embodiments, the method includes modulating human mu opioid receptorfunction at least 2-fold more than modulating arrestin function. Inembodiments, the method includes modulating mu opioid receptor functionat least 2-fold more than modulating human kappa opioid receptorfunction. In embodiments, the method includes modulating mu opioidreceptor function at least 2-fold more than modulating human deltaopioid receptor function. In embodiments, the method includes modulatingmu opioid receptor function at least 2-fold more than modulating humannociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorfunction at least 5-fold more than modulating arrestin function. Inembodiments, the method includes modulating mu opioid receptor functionat least 5-fold more than modulating human kappa opioid receptorfunction. In embodiments, the method includes modulating mu opioidreceptor function at least 5-fold more than modulating human deltaopioid receptor function. In embodiments, the method includes modulatingmu opioid receptor function at least 5-fold more than modulating humannociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorfunction at least 10-fold more than modulating arrestin function. Inembodiments, the method includes modulating mu opioid receptor functionat least 10-fold more than modulating human kappa opioid receptorfunction. In embodiments, the method includes modulating mu opioidreceptor function at least 10-fold more than modulating human deltaopioid receptor function. In embodiments, the method includes modulatingmu opioid receptor function at least 10-fold more than modulating humannociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorfunction at least 100-fold more than modulating arrestin function. Inembodiments, the method includes modulating mu opioid receptor functionat least 100-fold more than modulating human kappa opioid receptorfunction. In embodiments, the method includes modulating mu opioidreceptor function at least 100-fold more than modulating human deltaopioid receptor function. In embodiments, the method includes modulatingmu opioid receptor function at least 100-fold more than modulating humannociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorfunction at least 1000-fold more than modulating arrestin function. Inembodiments, the method includes modulating mu opioid receptor functionat least 1000-fold more than modulating human kappa opioid receptorfunction. In embodiments, the method includes modulating mu opioidreceptor function at least 1000-fold more than modulating human deltaopioid receptor function. In embodiments, the method includes modulatingmu opioid receptor function at least 1000-fold more than modulatinghuman nociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorfunction at least 10000-fold more than modulating arrestin function. Inembodiments, the method includes modulating mu opioid receptor functionat least 10000-fold more than modulating human kappa opioid receptorfunction. In embodiments, the method includes modulating mu opioidreceptor function at least 10000-fold more than modulating human deltaopioid receptor function. In embodiments, the method includes modulatingmu opioid receptor function at least 10000-fold more than modulatinghuman nociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorG protein-mediated function at least 2-fold more than modulatingarrestin function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 2-fold more thanmodulating human kappa opioid receptor function. In embodiments, themethod includes modulating mu opioid receptor G protein-mediatedfunction at least 2-fold more than modulating human delta opioidreceptor function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 2-fold more thanmodulating human nociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorG protein-mediated function at least 5-fold more than modulatingarrestin function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 5-fold more thanmodulating human kappa opioid receptor function. In embodiments, themethod includes modulating mu opioid receptor G protein-mediatedfunction at least 5-fold more than modulating human delta opioidreceptor function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 5-fold more thanmodulating human nociceptin receptor function.

In embodiments, the method includes modulating human mu opioid Gprotein-mediated receptor function at least 10-fold more than modulatingarrestin function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 10-fold more thanmodulating human kappa opioid receptor function. In embodiments, themethod includes modulating mu opioid receptor G protein-mediatedfunction at least 10-fold more than modulating human delta opioidreceptor function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 10-fold more thanmodulating human nociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorG protein-mediated function at least 100-fold more than modulatingarrestin function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 100-fold more thanmodulating human kappa opioid receptor function. In embodiments, themethod includes modulating mu opioid receptor G protein-mediatedfunction at least 100-fold more than modulating human delta opioidreceptor function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 100-fold more thanmodulating human nociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorG protein-mediated function at least 1000-fold more than modulatingarrestin function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 1000-fold more thanmodulating human kappa opioid receptor function. In embodiments, themethod includes modulating mu opioid receptor G protein-mediatedfunction at least 1000-fold more than modulating human delta opioidreceptor function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 1000-fold more thanmodulating human nociceptin receptor function.

In embodiments, the method includes modulating human mu opioid receptorG protein-mediated function at least 10000-fold more than modulatingarrestin function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 10000-fold morethan modulating human kappa opioid receptor function. In embodiments,the method includes modulating mu opioid receptor G protein-mediatedfunction at least 10000-fold more than modulating human delta opioidreceptor function. In embodiments, the method includes modulating muopioid receptor G protein-mediated function at least 10000-fold morethan modulating human nociceptin receptor function.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

EXAMPLES Example 1. Structure-Based Discovery of Biased μ-OpioidReceptor Analgesics with Reduced Side Effects

Opiate addiction, coupled with the potentially lethal side effects ofopiates like respiratory depression, has driven optimization campaignsfor safer and more effective analgesics since the 19^(th) century.Although the natural products morphine and codeine, and thesemi-synthetic drug heroin, were more reliably effective analgesics thanraw opium, they retained its liabilities. The classification of opioidreceptors into μ, δ, and K subtypes raised hopes that subtype-specificmolecules would escape the liabilities of morphinan-based opiates.Despite the introduction of potent synthetic opioid agonists likemethadone and fentanyl and the discovery of endogenous opioid peptides,analgesics without the drawbacks of classic opioids have remainedelusive. Recent studies have suggested that opioid-induced analgesiaresults from μ-opioid receptor (μOR) signaling through the G proteinG_(i), while many side effects, including respiratory depression andconstipation, may be conferred via β-arrestin pathway signaling.Agonists specific to the μOR and biased toward the G_(i) signalingpathway are therefore sought both as therapeutic leads and as molecularprobes to understand μOR signaling.

The determination of the crystal structures of the μ, δ, K, andnociceptin opioid receptors provided an opportunity to seek new μORagonists via structure-based approaches. We thus targeted the μOR forstructure-based docking, seeking ligands with new chemotypes. Wereasoned that such new chemotypes might confer signaling properties withnew biological effects.

We docked over 3 million commercially available lead-like compoundsagainst the orthosteric pocket of inactive μOR, prioritizinginteractions both with known affinity determinants and interactions withputative specificity residues that differ among the four opioid receptorsubtypes. For each compound, an average of 1.3 million configurationswas evaluated for complementarity to the receptor using thephysics-based energy function in DOCK3.6. The top ranking molecules wereinspected for features not explicitly captured in the scoring-function.We manually examined the top 2500 (0.08%) of the docking-ranked list fortheir novelty, their interactions with key polar residues such asAsp147³³² (superscripts indicate Ballesteros-Weinstein numbering), whiledeprioritizing molecules with strained internal interactions.Ultimately, 23 high-scoring molecules with ranks ranging from 237 to2095 out of the over 3 million docked were selected for testing (FIG.1E). Compared to the 5,215 μOR ligands annotated in ChEMBL16, thesedocking hits had Extended Connectivity Fingerprint 4 (ECFP4) basedTanimoto coefficients (T_(c)) ranging from 0.28 to 0.31, which isconsistent with the exploration of novel scaffolds. Of the 23 tested,seven had μOR binding affinities (K_(i)) ranging from 2.3 μM to 14 μM,as observed in Table 1.

TABLE 1 Molecules with μOR activity identified in the initial screen.μOR Cmpd Structure Rank T_(c) ^(a) K_(i) (μM) 1

467 0.28 7.2 2

358 0.28 5.8 3

1281 0.30 13.8 4

1465 0.30 2.3 5

2418 0.31 4.7 6

2211 0.30 10.0 7

1140 0.30 2.5 ^(a)The ECFP_4 Tanimoto similarity (T_(c)) to the mostsimilar μOR ligand in ChEMBL16.

The new ligands are predicted to engage the μOR in new ways (FIGS.2A-2H). Most opioid ligands use a cationic amine to ion pair withAsp147^(3.32), a canonical interaction observed in structures of theμOR, δOR, KOR, and nociceptin receptor bound to ligands of differentscaffolds. As anticipated, the docked ligands recapitulated thisinteraction. Much less precedence exists for the formation of anadditional hydrogen bond with this anchor aspartate, often mediated inthe docking poses by a urea amide. In embodiments, the new ligands withthe urea carbonyl is modeled to hydrogen-bond with Tyr148^(3.33), whilethe rest of the ligands often occupy sites unexplored by morphinans. Toour knowledge, the double hydrogen bond coordination of Asp147^(3.32)modeled in the docking poses has not been anticipated or observed foropioid ligands previously.

Despite the structural novelty of the initial docking hits, inembodiments their affinities were low. To enhance affinity andselectivity, we docked 500 analogs of compounds 4, 5 and 7 that retainedthe key recognition groups but added packing substituents or extendedfurther toward the extracellular side of the receptor, where the opioidreceptors are more variable. Of the 15 top-scoring analogs that weretested, seven had K_(i) values between 87 nM and 4.7 μM (Table 2).

TABLE 2 Analogs tested at the μOR. μOR G_(i) Docking μOR K_(i) κOR K_(i)EC50 Cmpd Structure Score T_(c) ^(a) (μM) (μM) (μM)  8

−42.08 0.31 0.82  0.46 6.6   9

−48.30 0.31 <50% 1.36 ND 10

−51.73 0.31 4.75  <50% ND 11

−46.79 0.35 1.86  <50% ND 12

−51.88 0.35 0.042 0.46 0.18 13

−51.22 0.35 0.550 1.02 3.1  14

−50.42 0.37 0.087 0.51 0.44 15

−43.17 0.37 0.130 <50% ND ^(a)The ECFP_4 Tanimoto similarity (T_(c)) tothe most similar μOR ligand in ChEMBL16. ND = not detectable under theseexperimental conditions.

Encouragingly, several were specific for the μOR over KOR (12-15, Table2). We then investigated the more potent analogs for signaling potencyand efficacy. Although the structure we docked against was the inactivestate of the μOR, compounds 8 and 12-14 activated G_(i/o)(Table 2).Intriguingly, compound 12 (FIG. 3B) strongly activated G_(i/o) with lowlevels of 3-arrestin2 recruitment.

To optimize compound 12, we synthesized stereochemically pure isomersand introduced a phenolic hydroxyl (FIG. 3B). The synthesis of the (S,S)stereoisomer of 12 improved affinity (K_(i)) to 4.8 nM and had ansignaling EC₅₀ of 65 nM; it was the most potent and efficacious G_(i/o)signaling agonist among the four isomers. The phenolic hydroxyl,introduced to make compound (S,S)-21, was designed to exploit awater-mediated hydrogen bond with His297^(6.52), an interaction observedin the structure of μOR in complex with β-FNA and in other structures ofthe δOR and KOR. This hydroxyl was readily accommodated in the dockedμOR-12 complex, improving the predicted docking energy. Compound(S,S)-21 had an EC₅₀ of 4.6 nM in a G_(i/o) activation assay, with 76%efficacy, and a K_(i) of 1.1 nM in radioligand binding assays (Table 3),an improvement of 40-fold versus 12.

TABLE 3 Binding and signaling properties of compounds 12 and PZM21. 12PZM21 K_(i) (nM) μOR  42 1.1 δOR N.A. 506 κOR 464 18 nociceptin ND NDG_(i/o) (Glosensor) EC₅₀ (nM) | E_(max) (%) μOR 180 | 88  4.6 | 77  δORND 1900 | 78  κOR ND ND nociceptin 1400 | 43  ND Arrestin recruitment(PathHunter) EC₅₀ (nM) | E_(max) (%) μOR 940 | 9.4  ND ND = notdetectable under these experimental conditions.

The other three stereoisomers of (S,S)-21 activity is observed in FIG.3B suggesting a specific stereochemical requirement for both potency andefficacy in agreement with the docked poses of (S,S)-21 to the inactiveand active structures of OR. We refer to (S,S)-21 as compound PZM21henceforth.

Because PZM21 was discovered against the inactive structure of μOR, itsdocked complex to active μOR retains ambiguities. To investigate thisfurther, more detailed docking and molecular dynamics simulations wereconducted. The resulting model was tested by synthesizing molecules thatperturbed or exploited specific modeled interactions (FIG. 4).Neutralization of charge by amidation (compound PZM28) decreases potencyby 1000-fold, supporting a key ionic interaction between the PZM21tertiary amine and Asp147^(3.32) (FIG. 4). Compound PZM27, which addssteric bulk to the tertiary amine, was synthesized to disrupt putativehydrophobic interactions between the N-methyl group and Met151^(3.36)and Trp293^(6.48) consistent with its 30-fold loss of potency anddecreased efficacy (FIG. 4). Compounds PZM23, PZM24, and PZM25, whichwere synthesized to disrupt hydrogen bonding interactions in the modelbetween the urea and Asp147^(3.32), Tyr326^(7.43) and Gln124^(2.60),lose between 30 and 230-fold potency despite their decreased solvationpenalties (FIG. 4). These key ionic and hydrogen-bonding interactionsare maintained in 3 μs of molecular dynamics simulations of PZM21 incomplex with active μOR, as are interactions between the phenolichydroxyl and the bridging waters to His297^(6.52), further supportingtheir relevance to the modeled pose (FIG. 4). The thiophene of PZM21,modeled to fit in the more open specificity region of the μOR, can bereplaced with a larger benzothiophene without loss of potency (FIG. 4).Interactions of the thiophene with residues that differ among the opioidreceptor sub-types may contribute to PZM21 specificity. Morecompellingly, the simulations and docking predict that the PZM21thiophene comes within 6 Å of Asn127^(2.63) in the active μOR. To probethis experimentally, we synthesized an irreversible version of PZM21(compound PZM29) designed to form a covalent bond with μOR engineeredwith an Asn127Cys (N127C) mutation. Compound PZM29 binds irreversibly tothis mutant but not the wild-type receptor and retains its efficacy asan agonist, supporting the overall orientation of PZM21 as modeled andsimulated in the orthosteric μOR site.

PZM21 had no detectable KOR or nociceptin receptor agonist activity,while it is a 500-fold weaker δOR agonist (FIG. 5 and Table 3), makingit a selective μOR agonist. Indeed, PZM21 is an antagonist at KOR (K_(i)of 18 nM) (FIG. 5 and Table 3). To investigate specificity more broadly,PZM21 was counter-screened for agonism against 316 other GPCRs. Activityat 10 μM was observed at several peptide and protein receptors; however,no potent activity was confirmed with a full dose-response experiment atthese receptors. PZM21 therefore has high agonist specificity amongGPCRs. PZM21 was also tested for inhibition of the hERG ion channel andthe dopamine, norepinephrine, and serotonin neurotransmittertransporters. At hERG, PZM21 had an IC₅₀ between 2 to 4 μM, which is500-1000-fold weaker than its potency as a μOR agonist. Its inhibitionof the neurotransmitter transporters, which are also analgesia targets,was even weaker with IC₅₀ values ranging from 7.8 to 34 μM. Thus, PZM21is a potent, selective, and efficacious opioid agonist.

A major goal of this study was to find new chemotypes that might displaybiased signaling and perhaps, unlike canonical opioid drugs, have morefavorable in vivo profiles. Signaling by PZM21 and other μOR agonistsappears to be mediated primarily by the heterotrimeric G proteinG_(i/o), as its effect on cAMP levels were eliminated by pertussis toxinand no activity was observed in a calcium release assay (FIGS. 6A-6B). Amaximal concentration of PZM21 led to no detectable 3-arrestin2recruitment in the PathHunter assay (DiscoverRx) and a minimal level ofμOR internalization compared to DAMGO and morphine (FIGS. 6A-6B).β-arrestin2 recruitment was too low to even permit a formal calculationof bias. Since β-arrestin recruitment can depend on the expression levelof G protein-coupled receptor kinase 2 (GRK2), we also investigatedG_(i/o) signaling and arrestin recruitment in cells co-transfected withthis kinase. Even in the presence of over-expressed GRK2, PZM21 stillhas weak arrestin recruitment efficacy compared to DAMGO and even tomorphine. In fact, the signaling bias of PZM21 was undistinguishablefrom TRV130, a G_(i) biased opioid agonist now in Phase III clinicaltrials, whereas its G protein-bias substantially exceeded that ofherkinorin, which has also been purported to be a G_(i)-biased agonist.An intriguing distinction in these signaling studies is the lack ofagonist activity of PZM21 at KOR. While PZM21 is an 18 nM antagonist ofthis receptor, the other biased agonist, TRV130, activates KOR withsimilar potency to morphine. Additionally, despite having similar levelsof signaling bias, in modeling studies TRV130 and PZM21 appear to engagethe μOR in distinct ways.

Consistent with its μOR agonist activity, PZM21 displayed dose-dependentanalgesia in a mouse hot-plate assay, with a percent maximal possibleeffect (% MPE) of 87% reached 15 minutes after administration of thehighest dose of drug tested (FIG. 7). The highest dose of morphinetested plateaued at 92% after 30 minutes. Intriguingly, we observed noanalgesic effect for PZM21 in the tail-flick assay (FIG. 8). Such adistinction is unprecedented among opioid analgesics. The hot-plateexperiment assesses analgesia at both higher-level central nervoussystem (CNS) brain and spinal nociceptive circuits, while the tail flickexperiment is more specific for spinal reflexive responses.Subcategorizing the behavioral responses in the hot-plate experiment aseither affective (CNS mediated) or reflexive (spinally mediated) showedthat, unlike morphine, PZM21 solely confers analgesia to the affectivecomponent of pain. Though separation of these two analgesic pathways isunique to PZM21 among known opioid analgesics, it has been observed byselective chemogenetic activation or toxin-induced inactivation of CNSneurons in rodents. Indeed, PZM21 is also active in a formalin injectionnociception assay, likely from supraspinal activation of descendinginhibitory circuits. PZM21 analgesia results from μOR activation in vivoas genetic knockout of the μOR completely ablates the observed analgesicresponse in the hot-plate assay (FIG. 9A). Meanwhile, PZM21 isrelatively stable to metabolism by mouse liver microsomes, with only 8%metabolism over one hour. Signaling experiments with the resultingmetabolite pool show no evidence of a metabolite with more potentactivation of the OR, confirming that the observed analgesic activityresults primarily from the originally administered dose of PZM21.

Based on previous genetic studies with arrestin knockout mice andpharmacological studies with biased compounds, we anticipated that PZM21would confer longer-lasting analgesia with decreased respiratorydepression and constipation—both key dose limiting side effects ofclassic opioid agonists. Analgesia induced by PZM21 lasts up to 180minutes, substantially longer than that induced by a maximal dose ofmorphine and the biased agonist TRV130 (FIG. 7). Whereas PZM21 doesreduce defecation, its constipation effect is substantially less thanmorphine (FIG. 10). Respiratory depression was investigated by dosingunrestrained mice with equianalgesic doses of PZM21, TRV130 and morphine(40 mg/kg, 1.2 mg/kg, and 10 mg/kg, respectively), and measuringrespiration by whole body plethysmography. While morphine profoundlydepressed respiration frequency, PZM21 was undistinguishable fromvehicle (FIG. 11). By comparison, TRV130 significantly depressesrespiration at 15 minutes, correlating with its peak analgesic response.Although respiratory depression by OR may be partially mediated byactivation of G-protein coupled inwardly-rectifying potassium channels(GIRKs), systemically infused opioids can decrease respiratory frequencyeven in GIRK−/− mice³⁸, consistent with the G protein independentsignaling mechanisms first suggested by the arrestin knockout studies.The rapid respiratory depression observed for morphine and TRV130 mayreflect GIRK activation. At later time points, however, PZM21 inducesminimal respiratory depression despite providing robust analgesia.Conversely, morphine induces a prolonged course of respiratorydepression that does not subside with resolution of the analgesicresponse at 90 minutes. This dissociation in analgesia and respiratorydepression at later time points may reflect differential recruitment ofβ-arrestin2. Taken together, these studies support minimal β-arrestin2signaling in vivo by PZM21.

A major liability of current opioid analgesics is reinforcement andaddiction, which are both postulated to be mediated—at least in part—byactivation of the dopaminergic reward circuits. A biomarker for suchactivation in mice is an acute hyperlocomotive response, reflectingmesolimbic dopaminergic activation. Whereas morphine induced mousehyperlocomotion in an open field assay (FIGS. 12A-12B), a close-toequianalgesic dose of PZM21 had no apparent effect on locomotion versusvehicle. The decreased distance traveled does not reflect a catalepticeffect of the molecule. Consistent with decreased activation of rewardcircuits, administration of PZM21 also does not induce a conditionedplace preference response (FIG. 13), unlike morphine and other opioids.Though TRV130 does trend more toward inducing place preference, itsactivity is also not significant relative to vehicle; this lack ofconditioned place preference for both biased agonists may support a rolefor G protein bias in the lack of opioid-induced reinforcing behavior.The differences between morphine and PZM21 in conditioned placepreference do not simply reflect dissimilarities in CNS penetrationbetween the two drugs, as a substantial fraction of PZM21 crosses theblood brain barrier.

Biased signaling through G protein and arrestin pathways reflects thestabilization of conformations over 30 Å from the orthosteric site wherePZM21 binds.

This study supports a structure-based approach for GPCR liganddiscovery. This method can reliably identify entirely new scaffolds andchemotypes. These new chemotypes may stabilize receptor conformationsnot explored previously and thereby generate novel biological effects.With a novel chemotype in hand, the docked structure provides astraight-forward strategy for optimization. Here, we were able tooptimize an initial docking hit, compound 7, 1000-fold to the final leadmolecule, PZM21, by evaluating approximately 50 molecules. Though thiscampaign was inspired by existing μOR biased agonists like TRV130, thestructure-based approach led to a compound with novel properties whichare structurally distinct compared to previously explored opioidligands, with not only substantial signaling bias but also unexpectedopioid receptor selectivity. These features have contributed tofavorable biological effects, with long lasting anaglesia coupled toapparent elimination of respiratory depression, specificity for centralover reflex analgesia, lack of locomotor potentiation and conditionedplace preference, and hence a reduced potential for opioid-inducedreinforcement for PZM21 and molecules like it. The selectivity, potency,and biased signaling of PZM21 make it a tool molecule of a sortpreviously unavailable to interrogate μOR signaling.

Example 2. Syntheses Conditions

Synthesis of enantiopure 12 and PZM21: The stereochemically pure isomersof 12 and PZM21 were synthesized from corresponding (R)- and (S)-aminoacid amides, which were either commercially available or readilyprepared from the corresponding acid or ester. The primary amino groupwas dimethylated using an excess of aqueous formaldehyde and sodiumtriacetoxyborohydride in aqueous acetonitrile. The carboxamides 16a,bwere converted to primary amines by treatment withborane-tetrahydrofurane complex under reflux yielding the diamines17a,b. Henry reaction of thiophene-3-carbaldehyde with nitroethaneafforded the nitropropene derivative 18, which was converted into theracemic alkylamine 19. Activation with 4-nitrophenyl chloroformateyielded the carbamates 20, which were coupled with the enantiopureprimary amines 17a,b to achieve diastereomeric mixtures of thecorresponding ureas 12 and 21. HPLC separation using a semi-preparativeChiralpak AS-H column gave the overall eight pure stereoisomers of 12and 21 including PZM21.

To determine the absolute configuration of the final products andefficiently prepare PZM21, we synthesized enantiomerically enrichedcarbamate 20, coupled it with the corresponding primary amines. Forenantiomeric enrichment, we performed chiral resolution of the racemicprimary amine 19 via repetitive crystallization withdi-p-anisoyl-(S)-tartaric acid. After triple crystallization, weobtained 19 enriched in dextrorotatory enantiomer ([α]_(D) ²⁵=+20.5 0).The corresponding (R)-acetamide has been previously characterized asdextrorotatory ([α]_(D)20=+49.8°), so enantiomerically enriched 19 wastreated with acetic anhydride and triethylamine, and the specificrotation of the product was measured. Based on the value of specificrotation of the resulting acetamide ([α]_(D)21=−46.6°), we assigned theabsolute configuration of the major isomer to be (S). (S)-enriched 20was used for synthesis of the final urea derivatives and absoluteconfiguration of diastereomers in pairs was assigned based on theequality of retention time in chiral HPLC.

Synthesis of structural analogs PZM22-29: Structural analogs of PZM21were synthesized starting from stereochemically pure L-tyrosine amide(30) or L-tyrosine methylamide (31) (see scheme 2). N-methylation orN-benzylation and subsequent N-methylation followed by amide reductionled to the respective diamines 35-37. Coupling with the nitrophenylcarbamates 42-44 resulted in the phenethyl ureas PZM22-25 and compound38, and the benzothiophene analog PZM26. The N-benzyl protectedderivative 38 was converted into the respective secondary amine 39 bycatalytic hydrogenation. This intermediate was used to introduceadditional substituents leading to the N-cyclopropylmethyl derivativePZM27 and the N-formyl derivative PZM28.

The disulfide functionalized PZM21 analog PZM29 could be preparedstarting from the dimethylamine 35. Coupling with theN-butynylimidazole-1-carboxamide 45 led to the alkynyl functionalizedurea 46. Copper catalyzed cycloaddition with bis(2-azidoethyl) disulfideresulted in the desired triazole derivative PZM29.

Scheme 1 (below). Syntheses of stereochemically pure 12 and 21.Reactants and conditions: i) CH₂O, NaBH(OAc)₃, acetonitrile/water, rt,15-30 min, 77-98%; ii) 1M BH₃.THF, reflux, 20 h, 48-95%; iii)nitroethane, HCOOH/ethanolamine, 90° C., 7 h, 82%; iv) 1M LiAlH₄,reflux, 30 min, 56%; v) 4-nitrophenyl chloroformate, triethylamine, THF,0° C. to rt, 6 h, 75%; vi) corresponding primary amine, DMF, rt, 20 h,70-98%.

Scheme 2 (below): Syntheses of target compounds PZM22-29: i)benzaldehyde, NaBH(OAc)₃, acetonitrile/water, rt, 2 h, 75%; ii) CH₂O,NaBH(OAc)₃, acetonitrile/water, rt, 12 min, 88-90%; iii) 1M BH₃ in THF,reflux, 20 h, 11-95%; iv) TEA, DMF, rt (to 120° C.), 3-22 h, 9-93%; v)4-nitrophenyl chloroformate, Et₃N, THF, 0° C. to rt, 8 h, 49-85%; vi)H₂, Pd/C, 1,1,2-trichloroethane, MeOH, rt, 5 h, 87%; vii)cyclopropylcarbaldehyde, NaBH(OAc)₃, acetonitrile/water, rt, 12 h, 86%;viii) ammonium formate, acetonitrile, reflux, 24 h, 26%; ix) DMF, 50°C., 24 h, 80%; x) bis(2-azidoethyl) disulfide, CuSO₄×5H₂O, sodiumascorbate, DMF/water, rt, 6 h, 44%.

All chemicals and solvents were purchased from Sigma Aldrich, Acros, orAlfa Aesar and were used without additional purification. Anhydroussolvents were of the highest commercially available grade and werestored over molecular sieves under a nitrogen atmosphere.

Flash chromatography was performed on Merck silica gel 60 (40-63 μm) asstationary phase under positive pressure of dry nitrogen gas. Dry columnvacuum chromatography was performed on Alfa Aesar TLC high purity gradesilica gel without binder (12 μm) as a stationary phase and Florisil®(100-200 mesh) or celite for sample preparation. Elution was performedunder negative pressure from water aspirator. Preparative chiral HPLCwas performed on Agilent 1100 HPLC system with UV detection (λ=254 nmand λ=210 nm) using Chiralpak® AS-H semi-preparative column (250×10 mm,5 μm) with eluent specified for each particular compound. Purificationby preparative RP-HPLC was performed on Agilent 1100 preparative series,column: Zorbax Eclipse XDB-C8 PrepHT (21.2×150 mm, 5 μm [C8]), flowrate: 10 mL/min, employing solvent system as specified below.

HR-ESIMS analyses were conducted on a Bruker Daltonik microTOF II or aBruker maXis MS in the laboratory of the Chair of BioinorganicChemistry, Friedrich Alexander Universität. HPLC-MS and HPLC purityanalyses were performed with an Agilent binary gradient system using UVdetection (λ=254 nm) in combination with ChemStation software. TheZorbax Eclipse XDB-C8 (4.6 mm×150 mm, 5 μm) column was used with a flowrate of 0.5 mL/min in reversed phase mode (eluent: MeOH/H₂O+0.1% HCOOH,10% to 100% in 21 min, 100% 3 min). Mass detection was conducted with aBruker Esquire 2000 ion-trap mass spectrometer using APCI or ESIionization source or with Bruker amaZon SL mass spectrometer incombination with a Agilent 1100 or Dionex Ultimate 3000 UHPLC system;respectively. ¹H, and 13C spectra were recorded on a Brucker Avance 360or a Brucker Avance 600 FT-NMR-Spectrometer. Chemical shifts werecalculated as ppm relative to TMS (¹H) or solvent signal (¹³C) asinternal standards.

(R)-2-Amino-3-phenylpropanamide hydrochloride D-Phe-NH₂

Dry ammonia gas was bubbled through the ice-cold solution ofD-phenylalanine methyl ester hydrochloride (1.01 g, 4.7 mmol) inanhydrous methanol (12 mL) for 25 min. Then the flask was sealed and themixture was allowed to warm up to the ambient temperature and stirredfor 20 h (progress of the conversion was monitored by TLC). After theconsumption of the starting material, the reaction mixture was purgedwith dry nitrogen gas (10 min) and the solvent was removed under reducedpressure. The white solid residue was suspended in boiling ethanol (30mL), filtered and the precipitate was washed with ethanol (5 mL).Combined filtrate and washing were concentrated under reduced pressure.The white solid residue was dried under high vacuum. Yield: 0.89 g(95%). LCMS(ESI+): t_(R)=9.0 min, purity: 99%; m/z: no molecular ion. ¹HNMR (360 MHz, DMSO-d₆) δ 8.27 (br. s., 3H), 7.99 (s, 1H), 7.49 (s, 1H),7.18-7.41 (m, 5H), 3.97 (t, J=6.8 Hz, 1H), 3.12 (dd, J=14.0, 6.5 Hz,1H), 3.05 (dd, J=14.0, 7.0 Hz, 1H).1H NMR (360 MHz, DMSO-d₆, exchangewith D₂O) δ 7.21-7.40 (m, 5H), 3.97 (t, J=6.8 Hz, 1H), 3.11 (dd, J=14.1,6.3 Hz, 1H), 3.03 (dd, J=14.1, 7.2 Hz, 1H).13C NMR (91 MHz, DMSO-d₆) δ169.6, 135.2, 129.5 (2C), 128.4 (2C), 127.0, 53.4, 36.6. HR-EIMS: found164.0950; calcd. 164.0950 for C₉H₁₂N₂O ([M−HCl]⁺). [α]_(D) ²⁴=−17.4° (c5, H₂O).

(S)-2-Amino-3-phenylpropanamide hydrochloride D-Phe-NH₂

(S)-2-Amino-3-phenylpropanamide hydrochloride was synthesized followingthe synthetic protocol for (R)-2-amino-3-phenylpropanamidehydrochloride. From L-phenylalanine methyl ester hydrochloride (1.02 g,4.7 mmol) the desired product was obtained as a white solid (0.89 g,94%). LCMS(ESI+): t_(R)=9.0 min, purity: 99%; m/z: no molecular ion. ¹HNMR (360 MHz, DMSO-d₆) δ 8.24 (br. s., 3H), 8.00 (br. s., 1H), 7.48 (br.s., 1H), 7.18-7.37 (m, 5H), 3.97 (t, J=6.7 Hz, 1H), 3.11 (dd, J=14.0,6.5 Hz, 1H), 3.05 (dd, J=13.9, 7.1 Hz, 1H). ¹H NMR (360 MHz, DMSO-d₆,exchange with D₂O) δ 7.21-7.40 (m, 5H), 3.96 (dd, J=7.3, 6.4 Hz, 1H),3.10 (dd, J=14.0, 6.4 Hz, 1H), 3.01 (dd, J=14.0, 7.3 Hz, 1H). 13C NMR(91 MHz, DMSO-d₆) δ 169.7, 135.2, 129.5 (2C), 128.4 (2C), 127.0, 53.4,36.7. [α]_(D) ²²=+17.5° (c 0.9, H₂O).

(R)-2-(Dimethylamino)-3-phenylpropanamide (R)-16a

37% Aqueous formaldehyde (2 mL, 27 mmol) was added to a suspension of(R)-2-amino-3-phenylpropanamide hydrochloride (0.39 g, 1.94 mmol) inacetonitrile (10 mL), followed by addition of sodiumtriacetoxyborohydride (1.65 g, 7.8 mmol). After 30 min of vigorousstirring the reaction was quenched with 1N NaOH, basified to pH>10, andextracted with ethyl acetate (3×20 mL). Combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The crude free base was dissolved in isopropanol (1.5 mL) andhydrochloride salt was precipitated via addition of 2N HCl in diethylether (1.5 mL, 3 mmol) and dilution with diethyl ether (10 mL). Theslurry was filtered and the white solid was washed with diethyl ether(2×5 mL). The product was obtained as a white solid (0.34 g, 77%) afterdrying under high vacuum. LCMS(ESI+): t_(R)=10.7 min, purity: n/a (220nm); m/z found: 193.4; calcd. 193.2 ([M-Cl]⁺). 1H NMR (360 MHz, DMSO-d₆)δ 11.13 (br. s., 1H), 7.92 (s, 1H), 7.61 (s, 1H), 7.19-7.38 (m, 5H),4.05 (dd, J=10.9, 4.0 Hz, 1H), 3.31 (dd, J=12.9, 3.9 Hz, 1H), 3.07 (dd,J=12.9, 11.0 Hz, 1H), 2.82 (s, 6H). 13C NMR (91 MHz, DMSO-d₆) δ 167.0,135.1, 129.2 (2C), 128.4 (2C), 127.0, 66.9, 33.5. (NHMe₂ signals areoverlapping with DMSO signal). [α]_(D) ²³=−71.0° (c 0.7, H₂O). HR-EIMS:found 192.1261; calcd. 192.1263 for C₁₁H₁₆N₂₀ (M⁺).

(S)-2-(Dimethylamino)-3-phenylpropanamide (S)-16a

(S)-16a was synthesized following the protocol described for (R)-16a.From (S)-2-amino-3-phenylpropanamide hydrochloride (0.39 g, 1.94 mmol),37% formaldehyde (1.44 mL, 19.4 mmol), and sodium triacetoxyborohydride(1.64 g, 7.8 mmol) the desired product was obtained as a white solid(0.36 g, 80%). LCMS(ESI+): t_(R)=10.7 min, purity: n/a (220 nm); m/zfound: 193.4; calcd. 193.2 ([M-Cl]⁺). ¹H NMR (360 MHz, DMSO-d₆) δ 11.08(br. s., 1H), 7.89 (br. s., 1H), 7.58 (br. s., 1H), 7.15-7.43 (m, 5H),4.02 (dd, J=10.7, 3.9 Hz, 1H), 3.22-3.29 (m, 1H), 3.06 (dd, J=12.8, 10.8Hz, 1H), 2.80 (s, 6H). ¹H NMR (360 MHz, DMSO-d₆, exchange with D₂O) δ7.19-7.39 (m, 5H), 4.02 (dd, J=10.6, 4.3 Hz, 1H), 3.28 (dd, J=12.9, 4.3Hz, 1H), 3.05 (dd, J=13.0, 10.6 Hz, 1H), 2.82 (s, 6H). [α]_(D) ²³=+71.4°(c 0.7, H₂O).

(R)-2-(Dimethylamino)-3-(4-hydroxyphenyl)propanamide hydrochloride(R)-16b

To a suspension of D-tyrosinamide (0.50 g, 2.3 mmol) inacetonitrile/water (9:1 v/v, 7 mL), 37% aqueous formaldehyde (2.0 mL, 27mmol) was added followed by sodium triacetoxyborohydride (2.35 g, 11.1mmol). The mixture was stirred for 15 min at an ambient temperature andthen quenched by saturated NaHCO₃ (8 mL). The pH was adjusted to 8 byaddition of 5% aqueous Na₂CO₃, and the mixture was extracted withisopropanol/ethyl acetate (1:3 v/v, 4×25 mL). Combined organic layerswere dried over anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The residue was dissolved in isopropanol (7 mL) andtreated with 37% aqueous HCl (0.25 mL). The solution was concentrated to2-3 mL, the product was precipitated by diethyl ether (15 mL) andfiltered. White solid was washed with diethyl ether (2×10 mL) and driedunder high vacuum. Yield: 0.54 g (96%). TLC (NH₄OH/MeOH/CHCl₃2.5:22.5:75): R_(f)=0.62 (KMnO₄ stain). LCMS (ESI+): t_(R)=6.1-7.1 min,purity: 97% (254 nm); m/z found: 209.3, calcd.: 209.3 ([M-Cl]⁺). ¹H NMR(600 MHz, DMSO-d₆) δ 11.10 (br. s., 1H), 9.43 (s, 1H), 7.91 (s, 1H),7.59 (s, 1H), 7.02 (d, J=8.3 Hz, 2H), 6.71 (d, J=8.3 Hz, 2H), 3.96 (dd,J=10.9, 4.1 Hz, 1H), 3.17 (dd, J=13.0, 4.0 Hz, 1H), 2.95 (dd, J=12.9,10.9 Hz, 1H), 2.79 (s, 6H). ¹H NMR (600 MHz, D₂O) δ 7.20 (d, J=8.5 Hz,2H), 6.91 (d, J=8.3 Hz, 2H), 4.04 (dd, J=10.8, 5.1 Hz, 1H), 3.42 (dd,J=13.0, 5.1 Hz, 1H), 2.87-3.17 (m, 7H). ¹³C NMR (91 MHz, DMSO-d₆) δ167.3, 156.4, 130.1 (2C), 124.9, 115.3 (2C), 67.1, 32.7. ¹³C NMR (91MHz, D₂O, acetone as internal standard) δ 170.5, 155.7, 131.4 (2C),126.0, 116.4 (2C), 70.1, 42.4 (2C), 34.0. HR-EIMS: m/z found: 209.1291,calcd.: 209.1290 for C₁₁H₁₇N₂O₂ ([M-Cl]⁺). [α]_(D) ²⁶=−55.7° (c 0.5,MeOH).

(S)-2-(Dimethylamino)-3-(4-hydroxyphenyl)propanamide hydrochloride(S)-16b

(S)-16b was synthesized following the synthetic protocol for (R)-16b.From L-tyrosinamide (0.54 g, 3.0 mmol), 37% aqueous formaldehyde (2.5mL, 33 mmol), and sodium triacetoxyborohydride (2.9 g, 13.5 mmol) thedesired product was obtained (0.57 g, 78%) as a white solid. LCMS(ESI+): t_(R)=6.1-7.1 min, purity: 98% (254 nm); m/z found: 209.3,calcd.: 209.3 ([M-Cl]⁺). ¹H NMR (360 MHz, DMSO-d₆) δ 10.99 (br. s., 1H),9.39 (br. s., 1H), 7.88 (s, 1H), 7.58 (s, 1H), 7.02 (d, J=8.6 Hz, 2H),6.71 (d, J=8.6 Hz, 2H), 3.95 (dd, J=10.8, 3.9 Hz, 1 H), 3.17 (dd,J=13.0, 3.9 Hz, 1H), 2.95 (dd, J=13.0, 10.8 Hz, 1H), 2.79 (s, 6H). ¹HNMR (360 MHz, DMSO-d₆, exchange with D₂O) δ 7.04 (d, J=8.4 Hz, 2H), 6.71(d, J=8.5 Hz, 2H), 3.95 (dd, J=10.4, 4.5 Hz, 1H), 3.17 (dd, J=13.2, 4.5Hz, 1H), 2.93 (dd, J=13.1, 10.6 Hz, 1H), 2.82 (d, J=7.7 Hz, 6H). 13C NMR(91 MHz, DMSO-d₆) δ 167.2, 156.3, 130.1 (2C), 124.8, 115.2 (2 C), 67.1,32.6. HR-EIMS: found 208.1214; calcd. 208.1212 for C₁₁H₁₆N₂O₂([M−HCl]⁺). [α]_(D) ²⁶=+58.6° (c 0.59, MeOH).

(R)—N²,N²-dimethyl-3-phenylpropane-1,2-diamine dihydrochloride (R)-17a

1M Borane-tetrahydrofurane complex (8.5 mL, 8.5 mmol) was slowly addedto a suspension of (R)-16a (0.32 g, 1.40 mmol) in anhydrous THF (5 mL)under cooling with ice bath under nitrogen atmosphere. The mixture wasrefluxed for 20 h and then quenched by slow addition of anhydrousmethanol (15 mL). The solvent was removed under reduced pressure and thedilution/evaporation sequence was repeated twice. The obtained oilyresidue was dissolved in isopropanol (5 mL) and 2N HCl in diethyl ether(1.4 mL, 2.8 mmol) was added, followed by dilution with diethyl ether(50 mL). The slurry was sonicated and filtered. Free-flowing white solidwas obtained (0.25 g, 72%) after drying under high vacuum. TLC(NH₄OH/MeOH/CHCl₃ 1.5:13.5:85): R_(f) (prod)=0.22. LCMS(ESI+): t_(R)=9.0min, purity: n/a (220 nm); m/z found: 179.4; calcd. 179.3 ([M−H-2Cl]⁺).1H NMR (360 MHz, DMSO-d₆) δ 11.15 (br. s., 1H), 8.56 (br. s., 3H),7.18-7.44 (m, 5H), 3.78-4.00 (m, 1H), 3.32-3.48 (m, 1H), 3.27 (dd,J=13.9, 3.9 Hz, 1H), 2.69-2.99 (m, 8H). ¹³C NMR (91 MHz, DMSO-d₆) δ135.7, 129.4 (2C), 128.8 (2C), 127.2, 64.1, 36.8, 30.8. [α]_(D)²³=+12.5° (c 1.1, H₂O). HR-ESIMS: found 179.1540; calcd. 179.1543 forC₁₁H₁₉N₂ ([M-Cl—HCl]⁺).

(S)—N²,N²-dimethyl-3-phenylpropane-1,2-diamine dihydrochloride (S)-17a

(S)-17a was synthesized following the protocol for (R)-17a. From (S)-16a(0.32 g, 1.40 mmol) and 1M borane-tetrahydrofurane complex (8.5 mL, 8.5mmol) the desired product was obtained as a free-flowing white solid(0.143 g, 48%) after additional purification by dry-column vacuumchromatography (gradient elution with NH₄OH/MeOH/CHCl₃ from 1:9:90 to2:18:80). LCMS(ESI+): t_(R)=9.0 min, purity: n/a (220 nm); m/z found:179.4; calcd. 179.3 ([M−H-2Cl]⁺). ¹H NMR (360 MHz, DMSO-d₆) δ 11.16 (br.s., 1H), 8.58 (br. s., 3H), 7.11-7.49 (m, 5H), 3.82-3.98 (m, 1H),3.37-3.48 (m, 1H), 3.28 (dd, J=14.1, 3.9 Hz, 1H), 2.73-2.96 (m, 8H). ¹HNMR (360 MHz, DMSO-d₆, exchange with D₂O) δ 7.25-7.47 (m, 5H), 3.79-3.95(m, 1H), 3.43 (dd, J=14.6, 8.8 Hz, 1H), 3.26 (dd, J=14.6, 4.3 Hz, 1H),2.77-2.98 (m, 8H). [α]D₂₃=−13.7° (c 0.9, H₂O).

(R)-4-[3-Amino-2-(dimethylamino)propyl]phenol dihydrochloride (R)-17b

1M Borane-tetrahydrofurane complex (12.0 mL, 12.0 mmol) was slowly addedto suspension of (R)-16b (0.45 mg, 1.85 mmol) in anhydrous THF (5 mL)under cooling with ice bath. The mixture was refluxed for 15 h undernitrogen atmosphere and then quenched with anhydrous methanol (10 mLdropwise, gas release). The solvent was removed under reduced pressureand dilution-evaporation sequence was repeated with anhydrous methanol(2×10 mL). The residue was resuspended in methanol (10 mL) with additionof 37% aqueous HCl (0.2 mL), concentrated under reduced pressure,diluted with ethanol and evaporated again (repeated twice). The residuewas suspended in diethyl ether (ca. 5 mL), sonicated, and filtered. Theproduct was washed with acetone (3×10 mL). Yield: 0.46 g (93%) of awhite solid after drying under high vacuum. TLC (NH₄OH/MeOH/CHCl₃2.5:22.5:75): R_(f)=0.23 (KMnO₄ stain). LCMS(ESI+): t_(R)=5.0 min,purity: 95%; m/z found: 195.4, calcd.: 195.3 ([M-2Cl-H]⁺). ¹H NMR (360MHz, DMSO-d₆) δ 11.10 (br. s., 1H), 9.49 (br. s., 1H), 8.58 (br. s.,3H), 7.13 (d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 3.63-3.92 (m, 1H),3.21-3.50 (m, 1H), 3.07-3.20 (m, 1H), 2.80 (br. m., 6H), 2.57-2.74 (m,2H). ¹H NMR (360 MHz, DMSO-d₆, exchange with D₂O) δ 7.15 (d, J=8.4 Hz,2H), 6.78 (d, J=8.4 Hz, 2H), 3.72 (br. s., 1H), 3.36 (dd, J=14.0, 7.6Hz, 1H), 3.11 (dd, J=14.0, 4.1 Hz, 1H), 2.58-2.96 (m, 8H). 13C NMR (91MHz, DMSO-d₆) δ 156.5, 130.2 (2C), 125.3, 115.5 (2C), 64.4, 36.6, 30.1.[α]_(D) ²⁵=+5.1° (c 0.96, H₂O).

(S)-4-[3-Amino-2-(dimethylamino)propyl]phenol dihydrochloride (S)-17b

(S)-17b was synthesized following the synthetic protocol for (R)-17b.From (S)-16b (0.46 g, 1.89 mmol) and 1M borane-tetrahydrofurane complex(11.5 mL, 11.5 mmol) the desired product was obtained as a white solid(0.23 g, 46%) after additional purification by washing with acetonitrile(5 mL). LCMS(ESI+): t_(R)=4.3-4.9 min, purity: 95%; m/z found: 195.4,calcd.: 195.3 ([M-2Cl-H]⁺). ¹H NMR (360 MHz, DMSO-d₆) δ 11.13 (br. s.,1H), 9.52 (br. s., 1H), 8.63 (br. s., 3H), 7.14 (d, J=8.5 Hz, 2H), 6.78(d, J=8.5 Hz, 2H), 3.68-4.00 (m, 1H), 3.24-3.56 (m, 1H), 3.16 (dd,J=14.3, 3.7 Hz, 1H), 2.80-2.94 (m, 6H), 2.67-2.79 (m, 2H). ¹H NMR (600MHz, DMSO-d₆, exchange with D₂O) δ 7.14 (d, J=8.5 Hz, 2H), 6.77 (d,J=8.5 Hz, 2H), 3.80 (br. s., 1H), 3.34-3.39 (m, 1H), 3.14 (dd, J=14.0,3.5 Hz, 1H), 2.76-2.95 (m, 7H), 2.66-2.75 (m, 1H). 13C NMR (91 MHz,DMSO-d₆) δ 156.5, 130.2 (2C), 125.3, 115.5 (2C), 64.3, 36.6, 30.1. ¹³CNMR (91 MHz, D₂O, MeOH as external standard) δ 155.4, 130.7 (2C), 125.0,116.3 (2C), 64.4, 39.9 (2C), 37.2, 31.8. [ ]D₂₄=−10.1° (c 0.47, H₂O).HR-ESIMS: m/z found 195.1498; calcd. 195.1492 for C₁₁H₁₉N₂O([M-Cl—HCl]⁺).

(E)-3-(2-Nitroprop-1-en-1-yl)thiophene 18

Nitroethane (13 ml, 0.18 mmol) and thiophene-3-carbaldehyde (3.9 ml, 45mmol) were added to an ice-cold mixture of formic acid (7.5 mL, 0.20mol) and ethanolamine (8.5 mL, 0.14 mol). The reaction mixture washeated to 85-90° C. and stirred for 7 h. The resulting solution waspoured into cold water (300 mL), and the slurry was filtered. Theprecipitated product was washed with water (3×50 mL) yielding yellowsolid (7.4 g, 98%). From two batches, 8.4 g of the crude product wasrecrystallized from ethanol/water (4:1 v/v) yielding yellow crystallinesolid (7.0 g, 83%). LCMS (ESI+): t_(R)=19.5 min, purity: 98% (254 nm);no molecular ion. 1H NMR (360 MHz, CDCl₃) δ 8.08 (br. s, 1H), 7.60 (m,J=3.0, 1.3 Hz, 1H), 7.44 (ddd, J=5.1, 3.0, 0.5 Hz, 1H), 7.28 (ddd,J=5.1, 1.3, 0.4 Hz, 1H), 2.50 (d, J=0.9 Hz, 3H).13C NMR (151 MHz, CDCl₃)δ 146.2, 133.7, 129.9, 128.2, 127.5, 127.0, 14.2. HR-EIMS: m/z found:169.0197, calcd.: 169.0197 for C₇H₇NO₂S ([M]⁺).

(RS)-1-(Thiophen-3-yl)propan-2-amine 19a

The solution of 18 (6.9 g, 41 mmol) in anhydrous THF (30 mL) was addeddropwise to 1M LiAlH₄ in THF (200 mL, 200 mmol) at a rate adjusted tokeep the mixture under a gentle reflux. After complete addition of thestarting material, the reaction mixture was refluxed for 30 min, cooledto 0° C., and Na₂SO₄.10H₂O was slowly added until the mixturesolidified. The resulting slurry was diluted with water, followed byadditional Na₂SO₄.10H₂O (2×0.5 g). The suspension was stirred for 15 minat ice bath and then filtered through Celite; the filter cake was washedthoroughly with ethyl acetate (total volume 500 mL). The yellow filtratewas concentrated under reduced pressure and the brown residue wasdissolved in diethyl ether (100 mL). Ether solution was extracted with1N HCl (3×100 mL). Combined aqueous layers were basified with 25%aqueous NH₃, and back-extracted with ethyl acetate (3×100 mL). Combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The brown residue was dissolved indiethyl ether (50 mL), cooled to 0° C. and the product was precipitatedby 2N HCl in diethyl ether (15 mL, 30 mmol) and filtered off. Theprecipitate was recrystallized from acetonitrile (ca. 100 mL), washedwith cold acetone, and dried under high vacuum. Yield: 4.02 g (56%) asgray crystalline solid. LCMS (ESI+): t_(R)=12.3 min, purity: 98% (254nm); m/z found: 142.3, calcd.: 142.2 ([M-Cl]⁺). 1H NMR (600 MHz,DMSO-d₆) δ 8.18 (br. s., 3H), 7.52 (dd, J=4.9, 2.8 Hz, 1H), 7.32 (dddd,J=2.8, 1.3, 1.0, 0.6 Hz, 1H), 7.04 (dd, J=4.9, 1.3 Hz, 1H), 3.38-3.47(m, 1H), 3.01 (ddd, J=14.0, 4.9, 1.0 Hz, 1H), 2.76 (ddd, J=14.0, 9.1,0.6 Hz, 1H), 1.13 (d, J=6.4 Hz, 3H). 13C NMR (151 MHz, DMSO-d₆) δ 136.8,128.5, 126.4, 122.9, 47.3, 34.6, 17.7. HR-EIMS: m/z found: 142.0689,calcd.: 142.0690 for C₇H₁₂NS ([M-Cl]⁺).

(S)-1-(Thiophen-3-yl)propan-2-amine (S)-19a (Chiral Resolution)

Racemic 19 (1.05 g, 5.9 mmol) was dissolved in water (40 mL), thesolution was basified by 25% aq. NH₃, and extracted with chloroform(3×40 mL). Combined organic layers were dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The liquid residue wasdissolved in ethanol (10 mL) and added to a hot solution ofdi-p-anisoyl-D-tartaric acid (2.5 g, 5.9 mmol) in acetonitrile (20 mL).White precipitate formed immediately. The slurry was diluted with water(10 mL) and heated to the boiling point. Ethanol was added in smallportions until all the solids dissolved. Seeding crystals (˜5 mg) wereadded and the solution was allowed to cool down to ambient temperature.Crystalline precipitate was filtered off and washed with acetonitrile(2×6 mL). Washings were combined with mother liquor, heated to boilingand the solution was allowed to cool down to ambient temperature in anopen beaker. The crystals from the first crop were dissolved in 1N NaOH(25 mL) and the solution was extracted by chloroform (3×15 mL). Combinedextracts were dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure. The residue was dissolved in diethyl ether (30mL) and hydrochloride salt was precipitated by adding excess of 2M HClin diethyl ether. The solvent was removed under reduced pressure and theresulting white solid was dried under high vacuum, yielding a whitesolid (0.45 g). Specific optical rotation of the first crop (convertedto hydrochloride) [α]21_(D)=+15.5° (c 1.25, H₂O). The 2^(nd) crop ofcrystals formed as a voluminous precipitate after two days of standingin the open beaker. It was collected by filtration and washed withacetonitrile (3×3 mL). Then the diastereomeric salt was converted tohydrochloride as described above. White crystalline solid (0.32 g) wasobtained. Specific optical rotation [α]²¹ _(D)=−13.0° (H₂O, 20.4° C., c0.92).

Crystals from the first crop (0.45 g, 2.5 mmol) were converted to freeamine as described above, and dissolved in ethanol (10 mL). The solutionwas mixed with di-p-anisoyl-D-tartaric acid (1.05 g, 2.5 mmol) andacetonitrile (10 mL). Total amount of 120 mL of water-ethanol (3:1 v/v)was added to completely dissolve the solids under heating to boilingpoint. The hot solution was left in an open Erlenmeyer flask forcrystallization at 4° C. After 20 h precipitated crystals were collectedby filtration, washed with acetonitrile (2×4 mL) and dried by suction.Di-p-anisoyl-D-tartrate salt was converted to hydrochloride as describedabove. Yield: 0.32 g (60% after double crystallization).[α]_(D)²²=+19.2° (c 0.94, H₂O). Triple crystallization delivers the productwith [α]_(D) ²⁵=+20.5° (c 0.52, H₂O). Absolute configuration wasestablished by acylation of enantiomerically enriched amine with aceticanhydride and comparing measured optical rotation to published data.

(S)—N-[1-(Thiophen-3-yl)propan-2-yl]acetamide (S)—N—Ac-19a

Acetic anhydride (30 μL, 0.32 mmol) was slowly added to a solution of(S)-19 (50 mg, 0.28 mmol) and triethylamine (80 μL, 0.57 mmol) inchloroform (1.5 mL). The mixture was stirred for 3 hrs at ambienttemperature. Then the mixture was diluted with chloroform (3 mL), washedwith saturated NaHCO₃ (3×3 mL) and brine (3 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas dried under high vacuum yielding white crystalline product (49 mg,95%). LCMS(ESI+): t_(R)=20.0 min, purity: 97%; m/z found: 184.3; calcd.184.3 ([M+H]⁺). 1H NMR (360 MHz, CDCl₃) δ 7.27 (dd, J=4.9, 3.0 Hz, 1H),6.96-7.02 (m, 1H), 6.94 (dd, J=4.9, 1.2 Hz, 1H), 5.26 (br. s., 1H), 4.26(dquind, J=8.3, 6.6, 5.9 Hz, 1H), 2.83 (dd, J=14.3, 5.9 Hz, 1H), 2.79(dd, J=14.2, 6.6 Hz, 1H), 1.93 (s, 3H), 1.12 (d, J=6.7 Hz, 3H). 13C NMR(91 MHz, CDCl₃) δ 169.3, 138.1, 128.8, 125.6, 122.0, 45.5, 36.7, 23.5,20.2. HR-EIMS: found 183.0718; calcd. 183.0718 for C₉H₁₃NOS (M⁺).[α]_(D) ²¹=−46.6° (c 1.0, CHCl₃). Based on literature data ([α]_(D)²⁰=+49.8° for (R)-enantiomer; c 0.5, CHCl₃), the absolute configurationwas assigned to be (S) for the product and the amine precursor.

4-Nitrophenyl (RS)-[1-(thiophen-3-yl)propan-2-yl]carbamate 20

A 25 mL Schlenk flask was charged with racemic 19 (0.20 g, 1.13 mmol)and triethylamine (0.32 mL, 2.3 mmol) in anhydrous THF (5 mL) undernitrogen atmosphere and cooling with ice bath. A solution of4-nitrophenyl chloroformate (0.23 g, 1.13 mmol) in anhydrous THF (2 mL)was added dropwise followed by a rinse with anhydrous THF (1 mL). Thereaction mixture was allowed to warm up to an ambient temperature andstirred for 6 h. Then the slurry was diluted with dichloromethane (20mL) and filtered. The filtrate was washed with saturated aqueous NaHCO₃(3×15 mL) and brine (15 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified byflash chromatography (100% dichloromethane) yielding desired product asa white foam (0.26 g, 75%). TLC: (ethyl acetate/hexane 4:6): R_(f)=0.64.LCMS(ESI+): t_(R)=20.4 min, purity: 96%; m/z found: 329.3, calcd.: 329.3([M+Na]⁺). ¹H NMR (600 MHz, CDCl₃) δ 8.20-8.26 (m, 2H), 7.31 (dd, J=4.7,3.0 Hz, 1H), 7.24-7.29 (m, 2H), 7.05 (ddt, J=2.9, 1.4, 0.8, Hz, 1H),6.98 (dd, J=4.9, 1.1 Hz, 1H), 4.98 (d, J=7.7 Hz, 1H), 4.07 (dqt, J=7.6,6.7, 6.4 Hz, 1H), 2.90 (d, J=6.4 Hz, 2H), 1.25 (d, J=6.7 Hz, 3H). 13CNMR (91 MHz, CDCl₃) δ 155.9, 152.3, 144.7, 137.6, 128.6, 125.9, 125.1(2C), 122.3, 121.9 (2C), 48.0, 37.0, 20.3. HR-EIMS: m/z found: 306.0674,calcd.: 306.0674 for C₁₄H₁₄N₂O₄S (M⁺).

4-Nitrophenyl (S)-[1-(thiophen-3-yl)propan-2-yl]carbamate (S)-19

(S)-20 was synthesized following the protocol for racemic 20, usingenantiomerically enriched (S)-19 as starting material. Spectralcharacteristics were the same as for the racemic compound. LCMS(ESI+):t_(R)=20.4 min, purity: 98%; m/z found: 329.3, calcd.: 329.3 ([M+Na]⁺).¹H NMR (360 MHz, CDCl₃) δ 8.20-8.26 (m, 2H), 7.31 (dd, J=4.9, 3.0 Hz,1H), 7.24-7.29 (m, 2H), 7.05 (ddt, J=2.9, 1.4, 0.8, Hz, 1H), 6.98 (dd,J=4.9, 1.3 Hz, 1H), 4.96 (d, J=7.6 Hz, 1H), 4.07 (dqt, J=7.6, 6.7, 6.4Hz, 1H), 2.90 (d, J=6.4 Hz, 2H), 1.26 (d, J=6.7 Hz, 3 H). 13C NMR (91MHz, CDCl₃) δ 155.9, 152.3, 144.7, 137.6, 128.6, 125.9, 125.1 (2C),122.3, 121.9 (2C), 48.0, 37.0, 20.3. [α]_(D) ²²=−44.9° (c 0.5, CHCl₃).

1-[(R)-2-(Dimethylamino)-3-phenylpropyl]-3-[(RS)-1-(thiophen-3-yl)propan-2-yl]urea(R,RS)-12

Triethylamine (50 μL, 0.36 mmol) was added to a suspension of (R)-17a(85 mg, 0.34 mmol) and racemic 20 (104 mg, 0.34 mmol) in anhydrous DMF(1 mL) under nitrogen atmosphere. The mixture was stirred at ambienttemperature for 20 h and then diluted with isopropanol/ethyl acetate(1:3 v/v, 20 mL), washed with 1N NaOH (5×15 mL), and extracted with 0.1NHCl (3×20 mL). Combined aqueous extracts were basified with carbonatebuffer to pH 9 and back-extracted with ethyl acetate (3×25 mL). Combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. No further purification wasrequired. The product was obtained as a colorless oil (107 mg, 92%). TLC(NH₄OH/MeOH/CHCl₃ 1:9:90): R_(f)=0.50. Diastereomers were separated bysemi-preparative HPLC (AS-H chiral column, 0.1% diethyl amine inisopropanol/hexane 50:50, 6 mL/min, 6 min).

1-[(R)-2-(Dimethylamino)-3-phenylpropyl]-3-[(R)-1-(thiophen-3-yl)propan-2-yl]urea(R,R)-12

Chiral HPLC: AS-H column, 0.1% diethyl amine in isopropanol/hexane50:50, 6 mL/min, 6 min: t_(R)=4.3 min. LCMS(ESI+): t_(R)=21.3 min,purity: 99%; m/z found: 346.6; calcd. 346.5 ([M+H]⁺). 1H NMR (360 MHz,CDCl₃) δ 7.24 (dd, J=4.9, 3.0 Hz, 1H), 7.07-7.32 (m, 5H), 6.94-6.99 (m,1H), 6.92 (dd, J=4.9, 1.2 Hz, 1H), 4.88 (d, J=5.8 Hz, 1H), 4.37 (d,J=7.7 Hz, 1H), 3.96 (dquind, J=8.1, 6.7, 5.4 Hz, 1H), 3.20 (ddd, J=12.8,6.9, 4.2 Hz, 1H), 2.95 (dd, J=13.3, 3.6 Hz, 1H), 2.91 (ddd, J=12.8,10.0, 2.0 Hz, 1H), 2.80 (dd, J=14.0, 5.3 Hz, 1H), 2.76 (tt, J=10.0, 4.0Hz, 1H), 2.72 (dd, J=14.0, 7.0 Hz, 1H), 2.31 (s, 6H), 2.31 (dd, J=13.3,10.0 Hz, 1H), 1.07 (d, J=6.6 Hz, 3H). 13C NMR (91 MHz, CDCl₃) δ 157.7,139.4, 138.6, 129.0 (2C), 129.0, 128.6 (2C), 126.2, 125.3, 121.9, 65.4,46.4, 40.7, 40.1 (2C), 37.5, 31.5, 20.7. [ ]D₂₅=−1.5° (c 0.42, CHCl₃).HR-ESIMS: found 346.1952, calcd. 346.1948 for C₁₉H₂₈N₃OS ([M+H]⁺).

1-[(R)-2-(Dimethylamino)-3-phenylpropyl]-3-[(S)-1-(thiophen-3-yl)propan-2-yl]urea(R,S)-12

Chiral HPLC: AS-H column, 0.1% diethyl amine in isopropanol/hexane50:50, 6 mL/min, 6 min: t_(R)=5.3 min. LCMS(ESI+): t_(R)=20.6 min,purity: 99%; m/z found: 346.7; calcd. 346.5 ([M+H]⁺). 1H NMR (600 MHz,CDCl₃) δ 7.26-7.30 (m, 2H), 7.23 (dd, J=4.9, 3.0 Hz, 1H), 7.17-7.21 (m,1H), 7.12-7.15 (m, 2H), 6.94-6.96 (m, 1H), 6.92 (dd, J=4.9, 1.3 Hz, 1H),4.90 (br. d, J=5.8 Hz, 1H), 4.46 (br. s., 1H), 3.98 (dquind, J=8.1, 6.6,5.4 Hz, 1H), 3.18 (ddd, J=13.0, 6.8, 4.3 Hz, 1H), 2.94 (dd, J=13.3, 3.6Hz, 1H), 2.91 (ddd, J=13.3, 10.0, 1.4 Hz, 1H), 2.79 (dd, J=14.0, 5.5 Hz,1H), 2.74 (tt, J=10.0, 4.0 Hz, 1H), 2.73 (dd, J=14.0, 6.8 Hz, 1H), 2.31(s, 6H), 2.29 (dd, J=13.4, 10.3 Hz, 1H), 1.07 (d, J=6.6 Hz, 3H). [α]_(D)²³=−16.2° (c 0.46, CHCl₃). The absolute configuration at1-(thiophen-3-yl)propan-2-yl substituent was established by synthesizingthe final product with enantiomerically enriched (S)-20 of knownconfiguration, and comparing the retention time of the resulting productwith the retention time of diastereomers in the chiral HPLC.

1-[(S)-2-(Dimethylamino)-3-phenylpropyl]-3-[(RS)-1-(thiophen-3-yl)propan-2-yl]urea(S,RS)-12

(S,RS)-12 was synthesized following the protocol for (R,RS)-12. From(S)-17a (85 mg, 0.34 mmol), racemic 20 (109 mg, 0.36 mmol), andtriethylamine (55 μL, 0.40 mmol) the desired product was obtained as acolorless oil (109 mg, 93%). Diastereomers were separated bysemi-preparative HPLC (AS-H chiral column, 0.1% diethyl amine inisopropanol/hexane 10:90, 11 mL/min, 8.5 min).

1-[(S)-2-(Dimethylamino)-3-phenylpropyl]-3-[(R)-1-(thiophen-3-yl)propan-2-yl]urea(S,R)-12

Chiral HPLC: AS-H column, 0.1% diethyl amine in isopropanol/hexane10:90, 11 mL/min, 108 bar, 8.5 min: t_(R)=4.9 min. LCMS(ESI+):t_(R)=20.6 min, purity: 99%; m/z found: 346.7; calcd. 346.5 ([M+H]⁺). 1HNMR (360 MHz, CDCl₃) δ 7.22 (dd, J=4.9, 3.0 Hz, 1H), 7.08-7.32 (m, 5H),6.93-6.96 (m, 1H), 6.92 (dd, J=4.9, 1.3 Hz, 1H), 4.89 (br. d, J=5.6 Hz,1H), 4.46 (br. d, J=6.2 Hz, 1H), 3.97 (dquind, J=8.1, 6.6, 5.4 Hz, 1H),3.18 (ddd, J=13.0, 6.8, 4.3 Hz, 1H), 2.94 (dd, J=13.3, 3.6 Hz, 1H), 2.91(ddd, J=13.3, 10.0, 1.4 Hz, 1H), 2.80 (dd, J=14.3, 5.7 Hz, 1H), 2.74(tt, J=10.0, 4.0 Hz, 1H), 2.72 (dd, J=14.0, 6.8 Hz, 1H), 2.31 (s, 6H),2.29 (dd, J=13.3, 10.0 Hz, 1H), 1.07 (d, J=6.6 Hz, 3H). 13C NMR (91 MHz,CDCl₃) δ 157.7, 139.3, 138.6, 129.0 (2C), 129.0, 128.6 (2C), 126.2,125.2, 121.9, 65.7, 46.3, 40.6, 40.1 (2C), 37.5, 31.4, 20.7.[α]_(D)²⁹=+16.7° (c 0.44, CHCl₃). HR-ESIMS: found 346.1950, calcd. 346.1948 forC₁₉H₂₈N₃OS ([M+H]⁺).

1-[(S)-2-(Dimethylamino)-3-phenylpropyl]-3-[(S)-1-(thiophen-3-yl)propan-2-yl]urea(S,S)-12

Chiral HPLC: AS-H column, 0.1% diethyl amine in isopropanol/hexane10:90, 11 mL/min, 8.5 min: t_(R)=6.5 min. LCMS(ESI+): t_(R)=21.3 min,purity: 99%; m/z found: 346.6; calcd. 346.5 ([M+H]⁺). ¹H NMR (600 MHz,CDCl₃) δ 7.26-7.29 (m, 2H), 7.23 (dd, J=4.9, 2.9 Hz, 1H), 7.17-7.21 (m,1H), 7.12-7.16 (m, 2H), 6.94-6.97 (m, 1H), 6.92 (dd, J=4.9, 1.3 Hz, 1H),4.91 (br. d, J=5.9 Hz, 1H), 4.42 (br. s., 1H), 3.96 (dquind, J=8.1, 6.6,6.6, 6.6, 6.6, 5.4 Hz, 1H), 3.19 (ddd, J=12.8, 6.9, 4.2 Hz, 1H), 2.94(dd, J=13.3, 3.6 Hz, 1H), 2.91 (ddd, J=12.8, 10.0, 2.0 Hz, 1H), 2.80(dd, J=14.0, 5.4 Hz, 1H), 2.75 (tt, J=10.0, 4.1 Hz, 1H), 2.72 (dd,J=14.1, 6.9 Hz, 1H), 2.30 (s, 6H), 2.30 (dd, J=13.3, 10.0 Hz, 1H), 1.07(d, J=6.7 Hz, 3H). [α]_(D) ²³=+3.5° (c 0.70, CHCl₃).

1-[(R)-2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-((RS)-1-(thiophen-3-yl)propan-2-yl)urea(R,RS)-21

To a suspension of (R)-17b (102 mg, 0.382 mmol) in acetonitrile (3 mL),triethylamine (0.16 mL, 1.15 mmol) was added. The flask was sealed andheated to 60° C. Solution of racemic 20 (117 mg, 0.382 mmol) inacetonitrile (3 mL) was added. The mixture immediately turned yellow.The temperature was increased to 80° C. The mixture was stirred for 2 hand then filtered through a cotton pad and concentrated under reducedpressure. The residue was suspended in 33% isopropanol/ethyl acetate (9mL) and washed with carbonate buffer (pH 9, 5×5 mL). Organic layer wasextracted with 0.1N HCl (3×5 mL). Combined acidic aqueous layers werebasified with carbonate buffer to pH 9 and back-extracted with ethylacetate (3×10 mL). Combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude residue waspurified by dry-column vacuum chromatography (gradient elution withNH₄OH/MeOH/CHCl₃ from 0.5:4.5:95 to 1.5:13.5:85). Yield: 94 mg (68%) asa white solid after trituration with hexane. LCMS(ESI+): t_(R)=19.0 min,purity: 98%; m/z found: 362.6, calcd.: 362.5 ([M+H]⁺). 1H NMR (—HCl)(360 MHz, DMSO-d₆) δ 10.27 (br. s., 1H), 9.31 (br. s., 1H), 7.42 (ddd,J=4.9, 3.0, 1.9 Hz, 1H), 7.15 (d, J=2.8 Hz, 1H), 7.08 (d, J=7.9 Hz, 2H),6.96 (dd, J=4.9, 1.2 Hz, 1H), 6.72 (d, J=8.4 Hz, 2H), 5.99-6.37 (m, 2H),3.79 (dt, J=13.3, 6.7 Hz, 1H), 2.87-3.26 (m, 4H), 2.53-2.85 (m, 9H),0.97 (d, J=6.6 Hz, 3H). 13C NMR (91 MHz, DMSO-d₆) δ 157.7, 155.9, 139.2,130.0 (2C), 128.8, 125.3, 121.6, 115.2 (2C), 79.1, 66.5 (br. s, 2C),45.8, 37.7, 36.9, 30.8, 20.7. Diastereomers were separated bysemi-preparative HPLC (AS-H chiral column, 0.1% diethyl amine inisopropanol/hexane 50:50, 8 mL/min, 8.5 min).

1-[(R)-2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-((R)-1-(thiophen-3-yl)propan-2-yl)urea(R,R)-21

Chiral HPLC: AS-H column, 0.1% diethyl amine in isopropanol/hexane50:50, 8 mL/min: t_(R)=4.2 min. LCMS(ESI+): t_(R)=19.0 min, purity: 98%;m/z found: 362.7, calcd.: 362.5 ([M+H]⁺). 1H NMR (600 MHz, CDCl₃) δ 7.23(dd, J=4.9, 3.0 Hz, 1H), 6.97-7.00 (m, 1H), 6.96 (d, J=8.3 Hz, 2H), 6.94(dd, J=4.9, 1.0 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 5.13 (br. s., 1H), 4.53(br. s., 1H), 3.97 (spt, J=6.7 Hz, 1H), 3.31 (m, J=12.7 Hz, 1H), 2.91(dd, J=12.7, 10.2 Hz, 1H), 2.87 (dd, J=13.4, 3.2 Hz, 1H), 2.80 (dd,J=13.9, 5.4 Hz, 1H), 2.72 (dd, J=14.1, 6.9 Hz, 1H), 2.64-2.72 (m, 1H),2.33 (s, 6H), 2.25 (dd, J=13.2, 10.7 Hz, 1H), 1.08 (d, J=6.6 Hz, 3H).[α]_(D) ²³=−30.4° (c 0.39, CHCl₃).

1-[(R)-2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(R,S)-21

Chiral HPLC: AS-H column, 0.1% diethyl amine in isopropanol/hexane50:50, 8 mL/min: t_(R)=6.3 min. LCMS(ESI+): t_(R)=19.0 min, purity: 98%;m/z found: 362.7, calcd.: 362.5 ([M+H]⁺). ¹H NMR (600 MHz, CDCl₃) δ 7.23(dd, J=4.9, 2.9 Hz, 1H), 6.96-6.99 (m, 1H), 6.95 (d, J=8.4 Hz, 2H), 6.93(dd, J=4.9, 1.0 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 5.12 (br. s., 1H), 4.59(br. s., 1H), 3.97 (spt, J=6.7 Hz, 1H), 3.29 (s, 1H), 2.91 (dd, J=12.9,10.2 Hz, 1H), 2.86 (dd, J=13.4, 3.3 Hz, 1H), 2.80 (dd, J=14.0, 5.7 Hz,1H), 2.73 (dd, J=14.0, 6.9 Hz, 1H), 2.68 (tt, J=10.2, 3.8 Hz, 1H), 2.33(s, 6H), 2.24 (dd, J=13.3, 10.7 Hz, 1H), 1.08 (d, J=6.5 Hz, 3H). [α]_(D)³⁰=−34.1° (c 0.28, CHCl₃). The absolute configuration at1-(thiophen-3-yl)propan-2-yl substituent was established by synthesizingthe final product with enantiomerically enriched (S)-20 of knownconfiguration, and comparing the retention time of the resulting productwith the retention time of diastereomers in the chiral HPLC.

1-[(S)-2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-((RS)-1-(thiophen-3-yl)propan-2-yl)urea(S,RS)-21

Triethylamine (0.16 mL, 1.15 mmol) was slowly added to a suspension of(S)-17b (106 mg, 0.40 mmol) and racemic 20 (121 mg, 0.40 mmol) inanhydrous DMF (2.5 mL) under nitrogen atmosphere. The mixture wasstirred for 20 h at ambient temperature, and then diluted withisopropanol/ethyl acetate (1:3 v/v, 12 mL). The organic layer was washedwith carbonate buffer (pH 9, 5×5 mL) and extracted with 0.1N HCl (3×5mL). Combined acidic aqueous layers were basified with carbonate bufferto pH 9 and back-extracted with ethyl acetate (3×10 mL). Combinedorganic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Further purification of the crudeyellow oil was accomplished by dry-column vacuum chromatography(gradient elution with NH₄OH/MeOH/CHCl₃ from 0.7:6.3:93 to 1:9:90),yielding the desired product (100 mg, 70%) as a white solid aftertrituration with hexane. Diastereomers were separated bysemi-preparative HPLC (AS-H chiral column, 0.1% diethyl amine inisopropanol/hexane 35:65, 7 mL/min, 9 min).

1-[(S)-2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-((S)-1-(thiophen-3-yl)propan-2-yl)ureaPZM21

Chiral HPLC: AS-H column, 0.1% diethyl amine in isopropanol/hexane35:65, 7 mL/min, 9 min: t_(R)=7.1 min. The stereoisomeric purity wasdetermined to be >99%. LCMS(ESI+): t_(R)=19.0 min, purity: 99%; m/zfound: 362.7, calcd.: 362.5 ([M+H]⁺). 1H NMR (360 MHz, CDCl₃) δ ppm 7.22(dd, J=4.9, 3.0 Hz, 1H), 6.95-6.97 (m, 1H), 6.94 (d, J=8.5 Hz, 2H), 6.92(dd, J=4.9, 1.2 Hz, 1H), 6.76 (d, J=8.4 Hz, 2H), 5.18 (br. d, J=5.2 Hz,1H), 4.70 (br. s., 1H), 3.95 (spt, J=6.8 Hz, 1H), 3.29 (ddd, J=13.2,6.6, 4.0 Hz, 1H), 2.91 (ddd, J=13.3, 9.7, 2.2 Hz, 1H), 2.85 (dd, J=13.3,3.3 Hz, 1H), 2.79 (dd, J=14.1, 5.4 Hz, 1H), 2.70 (dd, J=14.1, 6.6 Hz,1H), 2.66 (m, J=9.7, 6.6, 3.3 Hz, 1H), 2.31 (s, 6H), 2.23 (dd, J=13.3,10.6 Hz, 1H), 1.07 (d, J=6.8 Hz, 3H). 13C NMR (91 MHz, CDCl₃) δ ppm158.2, 155.6, 138.5, 129.9 (2C), 129.4, 128.9, 125.3, 122.0, 115.7 (2C),65.7, 46.6, 40.4, 40.1 (2C), 37.5, 30.4, 20.6. [α]D₂₃=+40.3^(°) (c 1.0,CHCl₃). HR-ESIMS: m/z found 362.1901; calcd. 362.1897 for C₁₉H₂₈N₃O₂S([M+H]⁺).

1-[(S)-2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl]-3-((R)-1-(thiophen-3-yl)propan-2-yl)urea(S,R)-21

Chiral HPLC: AS-H column, 0.1% diethyl amine in isopropanol/hexane35:65, 7 mL/min, 9 min: t_(R)=5.4 min. LCMS(ESI+): t_(R)=19.0 min,purity: 99%; m/z found: 362.7, calcd.: 362.5 ([M+H]⁺). ¹H NMR (600 MHz,CDCl₃) δ 7.22 (dd, J=4.8, 2.9 Hz, 1H), 6.96-6.98 (m, 1H), 6.94 (d, J=8.1Hz, 2H), 6.93 (dd, J=4.8, 1.0 Hz, 1H), 6.76 (d, J=8.1 Hz, 2H), 5.13 (br.d, J=6.1 Hz, 1H), 4.67 (br. s, 1H), 3.96 (spt, J=6.7 Hz, 1H), 3.23-3.33(m, 1H), 2.91 (ddd, J=13.3, 9.8, 2.2 Hz, 1H), 2.85 (dd, J=13.2, 3.2 Hz,1H), 2.80 (dd, J=14.2, 5.5 Hz, 1H), 2.72 (dd, J=14.2, 7.0 Hz, 1H), 2.66(tt, J=10.2, 3.8 Hz, 1H), 2.31 (s, 6H), 2.23 (dd, J=13.3, 10.7 Hz, 1H),1.07 (d, J=6.6 Hz, 3H). 13C NMR (91 MHz, CDCl₃) δ 158.1, 155.4, 138.5,129.9 (2C), 129.6, 129.0, 125.3, 122.0, 115.7 (2C), 65.9, 46.6, 40.4,40.1 (2C), 37.5, 30.4, 20.7. [α]_(D) ²⁵=+32.2° (c 0.58, CHCl₃).HR-ESIMS: m/z found 362.1901; calcd. 362.1897 for C₁₉H₂₈N₃O₂S ([M+H]⁺).The absolute configuration at 1-(thiophen-3-yl)propan-2-yl substituentwas established by synthesizing the final product with enantiomericallyenriched (S)-20 of known configuration, and comparing the retention timeof the resulting product with the retention time of diastereomers in thechiral HPLC.

(S)-1-(2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-phenethylurea×HCOOHPZM22

Compound 35 (72 mg, 0.27 mmol) was suspended in dry DMF (2.5 mL) in amicrowave tube. Triethylamine (20 μL, 0.14 mmol)) and 4-nitrophenylphenethylcarbamate (42) (70 mg, 0.24 mmol)) were added and the mixturewas stirred at room temperature under argon atmosphere for 3 hours.Then, the solution was diluted with isopropanol/EtOAc (1:3) and washedwith a saturated aqueous solution of NaHCO₃. The organic layer wasextracted with 0.1N HCl-solution and the aqueous extracts were adjustedto pH 9 with saturated aqueous NaHCO₃/Na₂CO₃ solution and finallyextracted with EtOAc. The organic layers were dried (Na₂SO₄), filteredunder reduced pressure. The residue was purified by preparative HPLC(acetonitrile in 0.1% and concentrated aqueous HCOOH, 5% to 30%acetonitrile in 13 min) to give pure PZM22 as a white powder in 37%yield (34.6 mg) after lyophilisation. LCMS (ESI+) t_(R)=4.2-4.8 min, m/zfound 342.2, calcd 342.2 [M+H]⁺. HR EIMS m/z found 342.2186, calcd342.2176 for C₂₀H₂₇N₃O₂ [M+H]⁺. Purity: 99%. ¹H NMR (600 MHz, DMSO) δ8.29 (s, 1H), 7.29-7.24 (m, 2H), 7.20-7.15 (m, 3H), 6.99-6.93 (m, 2H),6.70-6.65 (m, 2H), 6.11 (t, J=5.6 Hz, 1H), 5.71-5.63 (m, 1H), 3.16 (dd,J=13.4, 6.0 Hz, 2H), 3.09-3.04 (m, 1H), 2.84-2.76 (m, 1H), 2.71 (dd,J=13.5, 4.2 Hz, 1H), 2.63 (t, J=7.3 Hz, 2H), 2.59-2.54 (m, 1H), 2.25 (s,6H), 2.19 (dd, J=13.5, 9.3 Hz, 1H). 13C NMR (91 MHz, DMSO) δ 157.75,155.32, 139.72, 129.97, 129.70 (2C), 128.54 (2C), 128.17 (2C), 125.84,115.01 (2C), 65.38, 40.79, 39.96 (2C), 39.14, 36.12, 30.30.

(S)-3-(2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl)-1-methyl-1-phenethylurea×HCOOHPZM23

PZM23 was prepared as described for PZM22 using(S)-4-[3-amino-2-(dimethylamino)propyl]phenol (35) (50.9 mg, 0.26 mmol)and 4-nitrophenyl methyl(phenethyl)carbamate (43) (90.0 mg, 0.30 mmol)as starting materials. The reaction mixture was stirred 8 h at 120° C.Purification by preparative HPLC (acetonitrile in 0.1% aqueous HCOOH, 5%to 45% acetonitrile in 13 min) gave the pure product in 9% yield (9.1mg). LCMS (ESI+) t_(R)=4.4-4.9 min, m/z found 356.0, calcd 356.2 [M+H]⁺.HR EIMS m/z found 356.2344, calcd 356.2333 for C₂₁H₂₉N₃O₂ [M+H]⁺.Purity: 98%. ¹H NMR (600 MHz, DMSO) δ 8.45 (s, 1H), 7.30-7.24 (m, 2H),7.23-7.15 (m, 3H), 7.00-6.92 (m, 2H), 6.69-6.63 (m, 2H), 5.75-5.65 (m,1H), 3.34-3.30 (m, 2H), 3.00-2.95 (m, 2H), 2.74-2.63 (m, 7H), 2.27 (dd,J=9.2, 4.1 Hz, 1H), 2.24 (s, 6H). 13C NMR (151 MHz, DMSO) δ 157.66,155.78, 139.86, 130.83, 130.17 (2C), 129.15 (2C), 128.74 (2C), 126.46,115.44 (2C), 65.35, 50.36, 40.53, 40.13 (2C), 34.58, 34.13, 31.68.

(S)-1-(2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl)-1-methyl-3-phenethylurea×HCOOHPZM24

PZM24 was prepared as described for PZM22 using(S)-4-(2-(dimethylamino)-3-(methylamino)propyl)phenol (37) (15.0 mg,72.0 μmol) and 4-nitrophenyl phenethylcarbamate (42) (18.7 mg, 66.0μmol) as starting materials. After purification by preparative HPLC(acetonitrile in 0.1% aqueous HCOOH, 5% to 47% acetonitrile in 13 min)the pure compound (10.3 mg, 39%) was obtained. LCMS (ESI+) t_(R)=3.3-4.2min, m/z found 356.0, calcd 356.2 [M+H]⁺. HR EIMS m/z found 356.2338,calcd 356.2333 for C₂₁H₂₉N₃O₂ [M+H]⁺. Purity: 99%. 1H NMR (600 MHz,DMSO) δ 8.37 (s, 1H), 7.30-7.25 (m, 2H), 7.21-7.15 (m, 3H), 6.99-6.92(m, 2H), 6.69-6.62 (m, 2H), 6.48-6.37 (m, 1H), 3.32 (dd, J=14.5, 8.1 Hz,1H), 3.20 (ddd, J=9.2, 7.0, 1.6 Hz, 2H), 2.94 (dd, J=14.5, 4.7 Hz, 1H),2.83-2.77 (m, 1H), 2.72-2.63 (m, 3H), 2.55 (s, 3H), 2.25-2.15 (m, 7H).13C NMR (91 MHz, DMSO) δ 157.97, 155.27, 139.85, 130.19, 129.66 (2C),128.55 (2C), 128.18 (2C), 125.82, 115.01 (2C), 64.60, 48.12, 41.77,40.04 (2C), 36.01, 34.06, 31.00, 30.62.

(S)-1-(2-(Dimethylamino)-3-(4-hydroxyphenyl)propyl)-1,3-dimethyl-3-phenethylurea×HCOOHPZM25

PZM25 was prepared as described for PZM22 using(S)-4-(2-(dimethylamino)-3-(methylamino)propyl)phenol (37) (20.0 mg,96.0 μmol) and 4-nitrophenyl methyl(phenethyl)carbamate (43) (52.5 mg,0.18 mmol) as starting materials. The reaction mixture was stirred 4 hat 120° C. after it had been stirred for 18 hr at ambient temperature.Purification by preparative HPLC (acetonitrile in 0.1% aqueous HCOOH, 5%to 48% acetonitrile in 14 min) gave the pure product in 20% yield (7.8mg). LCMS (ESI+) t_(R)=4.2-4.8 min, m/z found 370.0, calcd 370.2 [M+H]⁺.HR EIMS m/z found 370.2495, calcd 370.2489 for C₂₂H₃₁N₃O₂ [M+H]⁺.Purity: 100%. 1H NMR (600 MHz, DMSO) δ 8.39 (s, 1H), 7.29-7.25 (m, 2H),7.21-7.16 (m, 3H), 6.98-6.93 (m, 2H), 6.67-6.63 (m, 2H), 3.26 (dd,J=13.7, 8.5 Hz, 1H), 3.23-3.14 (m, 2H), 2.88 (dd, J=13.8, 5.3 Hz, 1H),2.86-2.80 (m, 1H), 2.78-2.70 (m, 2H), 2.66-2.60 (m, 4H), 2.60 (s, 3H),2.19 (s, 6H), 2.18-2.14 (m, 1H). 13C NMR (151 MHz, DMSO) δ 163.97,155.29, 139.52, 130.27, 129.63 (2C), 128.59 (2C), 128.24 (2C), 125.96,114.98 (2C), 63.10, 51.58, 49.30, 40.07, 40.04, 36.88, 36.32, 33.16,31.36.

1-((S)-1-(Benzo[b]thiophen-3-yl)propan-2-yl)-3-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea×HCOOHPZM26

PZM26 was prepared as described for PZM22 using(S)-4-[3-amino-2-(dimethylamino)propyl]phenol (35) (25.0 mg, 0.13 mmol)and 4-nitrophenyl (1-(benzo[b]thiophen-3-yl)propan-2-yl)carbamate (44)(43.3 mg, 0.12 mmol) as starting materials. Yield: 31.7 mg (57%).Diastereomers were separated by semi-preparative HPLC (AS-H chiralcolumn, 0.1% diethyl amine in isopropanol/hexane 15:85, 12 mL/min, 25min, t_(R)(1-((R)-1-(benzo[b]thiophen-3-yl)propan-2-yl)-3-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea×HCOOH):12.5 min, t_(R)(1-((S)-1-(benzo[b]thiophen-3-yl)propan-2-yl)-3-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea×HCOOH(PZM26)): 18.5 min). The pure compound was obtained after additionalpurification by preparative HPLC (acetonitrile in 0.1% aqueous HCOOH, 5%to 74% acetonitrile in 10 min). LCMS (ESI+) t_(R)=5.3-6.4 min, m/z found412.2, calcd 412.2 [M+H]⁺, HR EIMS m/z found 412.2062, calcd 412.2053for C₂₃H₂₉N₃O₂S [M+H]⁺. Purity: 96%. ¹H NMR (600 MHz, CDCl₃) δ 8.62 (s,1H), 7.90-7.86 (m, 1H), 7.85-7.81 (m, 1H), 7.37-7.29 (m, 2H), 7.16 (s,1H), 6.97-6.92 (m, 2H), 6.78-6.74 (m, 2H), 5.72 (s, 1H), 4.85 (s, 1H),4.17 (dp, J=13.5, 6.7 Hz, 1H), 3.34 (d, J=13.2 Hz, 1H), 3.12 (dd,J=14.2, 5.4 Hz, 1H), 2.98 (dd, J=13.3, 9.6 Hz, 1H), 2.93-2.80 (m, 3H),2.40 (s, 6H), 2.38-2.31 (m, 1H), 1.12 (d, J=6.6 Hz, 3H). 13C NMR (91MHz, DMSO) δ 158.17, 156.17, 139.48, 138.92, 133.52, 130.08 (2C),124.06, 123.86, 123.23, 122.73, 121.90, 115.35 (2C), 66.86, 45.19,40.51, 39.92 (2C), 37.69, 35.54, 30.65, 20.41.

(S)-1-(2-((Cyclopropylmethyl)(methyl)amino)-3-(4-hydroxyphenyl)propyl)-3-phenethylurea×CF₃COOHPZM27

To compound 39 (23.9 mg, 0.07 mmol) in 3 mL of a 9:1 (v/v) mixture ofacetonitrile/H₂O (3 mL), AcOH (10 μL), cyclopropylcarboxaldehyde (55 μL,0.73 mmol) and sodium triacetoxyborohydride (155 mg, 0.73 mmol) wereadded consecutively. After stirring for 12 h at ambient temperature thereaction was quenched with a saturated aqueous solution of NaHCO₃ andadjusted to pH 8-9 with saturated aqueous NaHCO₃/Na₂CO₃ solution. Themixture was extracted with EtOAc, organic layers were dried (Na₂SO₄),filtered and evaporated. The residue was purified by preparative HPLC(acetonitrile in 0.1% aqueous CF₃COOH, 10% to 65% acetonitrile in 10min) to give the product as a white powder (31.1 mg, 86%) afterlyophilisation. LCMS (ESI+) t_(R)=4.8-5.5 min, m/z found 382.25, calcd382.25 [M+H]⁺. HR EIMS m/z found 382.2496, calcd 382.2489 for C₂₃H₃₁N₃O₂[M+H]⁺. Purity: 100%. ¹H NMR (3:2 isomer ratio, 600 MHz, D₂O) δ7.39-7.31 (m, 2H), 7.31-7.23 (m, 3H), 7.22-7.15 (m, 2H), 6.96-6.86 (m,2H), 3.82-3.71 (m, 1H), 3.49 (dd, J=15.3, 7.1 Hz), 3.40 (dd, J=15.5, 8.1Hz, 1H), 3.32 (t, J=6.5 Hz, 2H), 3.27-3.15 (m, 2H), 3.09-2.97 (m, 2H),2.95 (dd, J=13.2, 7.6 Hz), 2.90 (s, 1H), 2.87 (s, 2H), 2.82 (dd, J=14.3,9.1 Hz), 2.78-2.69 (m, 3H), 1.12-1.00 (m, 1H), 0.79-0.66 (m, 2H),0.44-0.30 (m, 2H). 13C NMR (3:2 isomer ratio, 151 MHz, DMSO) δ 159.88,158.81, 156.30, 156.28, 139.46, 139.36, 130.23, 130.14, 128.58, 128.57,128.27, 128.26, 126.17, 126.06, 126.03, 126.01, 115.49, 115.44, 66.81,66.75, 58.19, 56.08, 41.16, 41.03, 38.34, 37.56, 35.92, 35.85, 37.47,34.92, 31.19, 29.89, 6.34, 6.11, 4.70, 4.14, 3.97, 3.44.

(S)—N-(1-(4-Hydroxyphenyl)-3-(3-phenethylureido)propan-2-yl)-N-methylformamidePZM28

(S)-1-(3-(4-Hydroxyphenyl)-2-(methylamino)propyl)-3-phenethylurea (39)(14.7 mg, 45.0 μmol) was dissolved in a microwave tube in dryacetonitrile (1 mL). Ammonium formate (14.2 mg, 0.23 mmol) was added andthe reaction mixture was stirred at reflux temperature for 24 h. Thenthe solvent was evaporated and the obtained residue was purified byflash chromatography (CH₂Cl₂/MeOH 20:1) to give the compound as amixture of cis-/trans-isomers in 26% yield (4.2 mg). LCMS (ESI+)t_(R)=5.7-6.4 min, m/z found 356.21, calcd 356.20 [M+H]⁺. HR EIMS m/zfound 356.1968 and 378.1793, calcd 356.1969 and 378.1788 for C₂₀H₂₅N₃O₃[M+H]⁺ and [M+Na]⁺, respectively. Purity: 95%. 1H NMR (2:1 isomer ratio,500 MHz, CDCl₃) δ 7.86 (s, 1H), 7.47 (s, 1H), 7.41 (s, 1H), 7.29-7.10(m, 5H), 6.99-6.98 (m, 1H), 6.92-6.90 (m, 1H), 6.75-6.71 (m, 2H),5.14-4.54 (m, 2H), 3.67-3.58 (m, 2H), 3.42-3.38 (m, 2H), 3.22-3.05 (m,1H), 2.82-2.55 (m, 7H). ¹³C NMR (2:1 isomer ratio, 125 MHz, CDCl₃) δ164.39, 163.85, 158.29, 158.24, 155.57, 155,33, 139.06, 129.74, 128.81,128.55, 128.20, 127.88, 126.38, 115.78, 115.58, 61.13, 41.57, 41.40,40.67, 40.49, 36.33, 36.29, 35.38, 34.76, 30.82, 29.67.

(S)-1-(2-(1-(2-((2-Azidoethyl)disulfanyl)ethyl)-1H-1,2,3-triazol-4-yl)ethyl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea×CF₃COOHPZM29

PZM29 was synthesized via CuAAc reaction:(S)-1-(But-3-yn-1-yl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea(46) (31.5 mg, 0.11 mmol), CuSO₄×5H₂O (7.10 mg, 28.4 μmol), sodiumascorbate (8.10 mg, 41.0 μmol) and bis(2-azidoethyl) disulfide (46.3 mg,0.23 mmol) were dissolved in of DMF/H₂O (1.2 mL, 2:1 (v/v)) and stirredat room temperature for 6 h. The reaction mixture was quenched with 0.1MEDTA-solution, adjusted to pH 8-9 with saturated aqueous NaHCO₃/Na₂CO₃solution and extracted with EtOAc. Combined organic layers were dried(Na₂SO₄), filtered and concentrated under reduced pressure. The residuewas purified by preparative HPLC (acetonitrile in 0.1% aqueous CF₃COOH,5% to 50% acetonitrile in 12 min) to give the pure product in 44% (29mg) yield. LCMS (ESI+) t_(R)=3.5-4.5 min, m/z found 494.1, calcd 494.2[M+H]⁺. HR EIMS m/z found 494.2110, calcd 494.2115 for C₂₀H₃₁N₉O₂S₂[M+H]⁺. Purity: 98%. 1H NMR (600 MHz, DMSO) δ 9.64 (s, 1H), 9.37 (s,1H), 7.92 (s, 1H), 7.18-7.01 (m, 2H), 6.80-6.67 (m, 2H), 6.38 (s, 2H),4.61 (t, J=6.6 Hz, 2H), 3.59 (t, J=6.4 Hz, 2H), 3.49-3.40 (m, 1H),3.32-3.25 (m, 3H), 3.23 (t, J=6.6 Hz, 2H), 3.21-3.12 (m, 1H), 3.00 (dd,J=13.8, 3.5 Hz, 1H), 2.95 (t, J=6.4 Hz, 2H), 2.88 (d, J=4.9 Hz, 3H),2.81 (d, J=4.9 Hz, 3H), 2.74 (t, J=7.3 Hz, 2H), 2.60 (dd, J=13.7, 10.7Hz, 1H). ¹³C NMR (151 MHz, DMSO) δ 158.76, 156.28, 144.50, 130.19 (2C),126.14, 122.50, 115.44 (2C), 67.14, 49.11, 47.90, 40.90, 40.06, 38.32,37.85, 37.20, 36.70, 30.56, 26.22.

(S)-2-(Benzylamino)-3-(4-hydroxyphenyl)propanamide 32

To a suspension of L-tyrosinamide (30) (0.80 g, 4.47 mmol) in a 9:1(v/v) mixture of acetonitrile/H₂O (19 mL), AcOH (0.40 mL), benzaldehyde(0.47 g, 4.44 mmol) and sodium triacetoxyborohydride (2.82 g, 13.3 mmol)were added. The reaction mixture was stirred for 2 hours and quenchedwith a saturated aqueous solution of NaHCO₃. The pH was adjusted to pH8-9 by saturated aqueous NaHCO₃/Na₂CO₃ solution and extracted withisopropanol/EtOAc (1:3). The organic layers were dried (Na₂SO₄),filtered and evaporated. The product (901 mg, 75%) was obtained as awhite solid after purification by flash chromatography (CH₂Cl₂/MeOH/NH₃15:1:0.1). LCMS (ESI+) m/z found 271.0, calcd 271.1 [M+H]⁺.

(S)-2-(Benzyl(methyl)amino)-3-(4-hydroxyphenyl)propanamide 33

Compound 33 was prepared as described for compound (R)-16b. Startingfrom (S)-2-(benzylamino)-3-(4-hydroxyphenyl)propanamide (32) (0.80 g,2.96 mmol), 37% aqueous formaldehyde (1.20 mL, 14.8 mmol) and sodiumtriacetoxyborohydride (1.88 g, 8.88 mmol), the product was obtained(0.76 g, 90%) as a white solid after purification by flashchromatography (CH₂Cl₂/MeOH/NH₃ 20:1:0.1). LCMS (ESI+) m/z found 285.0,calcd 285.2 [M+H]⁺.

(S)-2-(Dimethylamino)-3-(4-hydroxyphenyl)-N-methylpropanamide 34

Compound 34 was prepared as described for compound (R)-16b. Startingfrom (S)-2-amino-3-(4-hydroxyphenyl)-N-methylpropanamide (31) (0.40 g,2.06 mmol), 37% aqueous formaldehyde (1.54 mL, 20.6 mmol) and sodiumtriacetoxyborohydride (2.20 g, 10.3 mmol) the pure product was obtained(0.40 g, 88%) as a white solid after purification by flashchromatography (CH₂Cl₂/MeOH/NH₃ 9:1:0.1). LCMS (ESI+) m/z found 222.92,calcd 223.14 [M+H]⁺.

(S)-4-[3-Amino-2-(dimethylamino)propyl]phenol 35

Compound 35 was synthesized following the synthetic protocol for(S)-17b. Starting from (S)-16b (4.10 g, 16.8 mmol) and 1Mborane-tetrahydrofurane complex (102 mL, 103 mmol), the product wasobtained as a yellowish white foam (3.10 g, 95%) after flashchromatography (CH₂Cl₂/MeOH/NH₃ 9:1:0.1). LCMS (ESI+) m/z found 194.90,calcd 195.15 [M+H]⁺.

(S)-4-(3-Amino-2-(benzyl(methyl)amino)propyl)phenol 36

Compound 36 was synthesized as described for compound 35 using(S)-2-(benzyl(methyl)amino)-3-(4-hydroxyphenyl)propanamide (0.70 g, 2.46mmol) as starting material. 36 (0.52 g, 78%) was obtained afterpurification by flash chromatography (CH₂Cl₂/MeOH/NH₃ 9:1:0.1). LCMS(ESI+) m/z found 271.03, calcd 271.18 [M+H]⁺.

(S)-4-(2-(Dimethylamino)-3-(methylamino)propyl)phenol 37

Compound 37 was prepared as described for compound 35 using(S)-2-(dimethylamino)-3-(4-hydroxyphenyl)-N-methylpropanamide (34) (0.38g, 1.71 mmol) as starting material. The product was obtained afterpurification by flash chromatography (CH₂Cl₂/MeOH/NH₃ 9:1:0.1) in 11%(38.2 mg) yield. LCMS (ESI+) m/z found 208.89, calcd 209.16 [M+H]⁺.

(S)-1-(2-(Benzyl(methyl)amino)-3-(4-hydroxyphenyl)propyl)-3-phenethylurea38

Compound 38 was prepared as described for PZM22 using(S)-4-(3-amino-2-(benzyl(methyl)amino)propyl)phenol (36) (0.1 g, 0.42mmol) and 4-nitrophenyl phenethylcarbamate (42) (0.10 g, 0.35 mmol) asstarting materials. Pure product was obtained after flash chromatography(CH₂Cl₂/MeOH/NH₃ 50:1:0.1→40:1:0.1→30:1:0.1) in 93% (0.14 g) yield. LCMS(ESI+) m/z found 418.22, calcd 418.25 [M+H]⁺.

(S)-1-(3-(4-Hydroxyphenyl)-2-(methylamino)propyl)-3-phenethylurea 39

Compound 38 (0.12 g, 0.30 mmol) was dissolved in MeOH (10 mL) in aSchlenk flask and stirred under N₂ atmosphere. 1,1,2-Trichloroethane (27μL, 0.30 mmol) and 10% Pd—C were added and the mixture was stirred for 5h under H₂ atmosphere at ambient temperature. The suspension wasfiltered through celite, the filtrate was evaporated and the residue waspurified by flash chromatography (CH₂Cl₂/MeOH/NH₃ 15:1:0.1) to give pure39 in 87% (81.3 mg) yield. LCMS (ESI+) m/z found 328.15, calcd 328.20[M+H]⁺.

4-Nitrophenyl methyl(phenethyl)carbamate 43

4-Nitrophenyl chloroformate (0.32 g, 1.56 mmol) in a Schlenk flask wassolved in dry THF (4 mL) and stirred under N₂ atmosphere in anice-water-bath. A mixture of N-methyl-(β-phenylethyl) amine (40) (0.20g, 1.48 mmol) and triethylamine (0.41 mL, 2.96 mmol) in dry THF (5 mL)was added dropwise. The reaction mixture was allowed to warm up to roomtemperature and was stirred for 8 h. The mixture was diluted withdichloromethane, filtered and the filtrate was washed with saturatedaqueous NaHCO₃ and brine. The organic layer was dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was purified byflash chromatography (100% dichloromethane) to give the product as awhite solid (85%, 0.38 g) after trituration with hexane. LCMS (ESI+) m/zfound 300.84, calcd 301.12 [M+H]⁺.

4-Nitrophenyl (1-(benzo[b]thiophen-3-yl)propan-2-yl)carbamate 44

Compound 44 was prepared as described for compound 43 using1-(1-benzothiophen-3-yl)propan-2-amine hydrochloride (0.11 g, 0.49mmol), 4-nitrophenyl chloroformate (97.5 mg, 0.49 mmol) andtriethylamine (0.14 mL, 0.97 mmol) as starting materials. Pure 44 wasobtained after purification by flash chromatography (100%dichloromethane). Yield: 84.7 mg (49%) as a white solid aftertrituration with hexane. LCMS (ESI+) m/z found 357.13, calcd 357.09[M+H]⁺.

(S)-1-(But-3-yn-1-yl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea46

N-3-Butyn-1-yl-1H-imidazole-1-carboxamide (45) (0.33 g, 2.01 mmol) and(S)-4-[3-amino-2-(dimethylamino)propyl]phenol (35) (0.50 g, 2.57 mmol)were solved in dry DMF (10 mL) and stirred for 24 h under Ar atmosphereat 50° C. H₂O was added and the mixture was lyophilisated. Afterpurification by flash chromatography (CH₂Cl₂/MeOH/NH₃ 9:1:0.1) theproduct was obtained as a white solid (0.47 g, 80%). LCMS (ESI+) m/zfound 290.05, calcd 290.19 [M+H]⁺

Overview of Molecular Dynamics Simulations

Simulation Total His297^(6.52) size simu- μOR protonation (# totalLength of lation structure state atoms) each simulation time Inactive δN(HID) 101,161 350 ns; 450 ns; 350 ns 2.0 μs Inactive εN (HIE) 101,167400 ns; 450 ns Active δN (HID) 101,473 950 ns; 900 ns; 950 ns 3.6 μsActive εN (HIE) 101,476 1000 ns; 950 ns; 950 ns

Example 3. Methods

Molecular Docking and Analog Selection:

The inactive state μ-opioid receptor structure (PDB: 4DKL) was used asinput for receptor preparation with DOCK Blaster(http://blaster.docking.org). Forty-five matching spheres were usedbased on a truncated version of the crystallized ligand. The covalentbond and linker region of the antagonist 3-funaltrexamine were removedfor sphere generation. The ligand sampling parameters were set with binsize, bin size overlap, and distance tolerances of 0.4 Å, 0.1 Å, and 1.5Å, respectively, for both the matching spheres and for the dockedmolecules. Ligand poses were scored by summing the receptor-ligandelectrostatics and van der Waals interaction energy corrected for liganddesolvation. Receptor atom partial chargers were used from the unitedatom AMBER force field except for Lys233 and Tyr326, where the dipolemoment was increased. Over 3 million commercially available moleculesfrom the ZINC (http://zinc.docking.org) lead-like set were docked intothe receptor using DOCK3.6 (http://dock.compbio.ucsf.edu). Among the topranking 0.08% of molecules were inspected and 23 were selected forexperimental testing in the primary screen.

For a secondary screen, analogs of the top three hits from the primaryscreen (Compounds 4, 5 and 7) with a similarity of greater than 0.7 (asdefined in the ZINC search facility) were identified in the ZINCdatabase. Additionally, substructure searches were performed using thescaffolds of each of these three compounds. The searches yielded 500purchasable compounds, which were then docked as in the primary screen.Analogs were manually inspected for interactions and selected forfurther experimental testing.

Radioligand Binding Studies:

For a primary screen of selected molecules, binding to μOR was assessedby measuring competition against the radioligand ³H-diprenorphine(³H-DPN). Each compound was initially tested at 20 μM and was incubatedwith ³H-DPN at a concentration equal to the K_(d) (0.4 nM) of theradioligand in μOR containing Sf9 insect cell membranes. The reactioncontained 40 fmol of μOR and was incubated in a buffer of 20 mM HEPES pH7.5, 100 mM sodium chloride, and 0.1% bovine serum albumin for 1 hour at25° C. To separate free from bound radioligand, reactions were rapidlyfiltered over Whatman GF/B filters with the aid of a Brandel harvesterand ³H-DPN counts were measured by liquid scintillation. Compounds withmore than 25% of ³H-DPN radioactivity were further tested in fulldose-response to determine the affinity (K_(i)) in HEK293 membranes.Subsequently, the 15 analogs were tested in full dose-response foraffinity at the μOR and the κOR by the National Institutes of MentalHealth Psychoactive Drug Screen Program (PDSP), as were the affinitiesof compounds 12, PZM21, and their stereoisomers at the μOR, δOR, κOR andnociception receptor.

Radioligand depletion assays to test the irreversible binding ofcompound PZM29 were performed as described previously. Human embryonickidney 293 (HEK 293) cells were transiently transfected with μOR or thecysteine mutant μOR:N127C using the Mirus TransIT-293 transfectionreagent (MoBiTec, Goettingen, Germany), grown for 48 hrs, harvested, andhomogenates were prepared as described. For radioligand depletionexperiments, homogenates were preincubated in TRIS buffer (50 mM Tris atpH 7.4) at a protein concentration of 50-100 g/mL or 70-120 μg/mL forμOR and OR:N127C, respectively and the covalent ligand (at 5 M) fordifferent time intervals. Incubation was stopped by centrifugation andreversibly bound ligand was washed three times (resuspension in bufferfor 30 min and subsequent centrifugation). Membranes were then used forradioligand binding experiments with ³H-diprenorphine (finalconcentration: 0.7 nM, specific activity: 30 Ci/mmol, purchased fromBiotrend, Cologne, Germany) to determine specific binding at the μOR(B_(max)=4000-6500 fmol/mg protein, K_(D)=0.25-0.45 nM) and theμOR:N127C receptor (B_(max)=1300-6000 fmol/mg protein, K_(D)=0.18-0.25nM), respectively as described. Non-specific binding was determined inthe presence of 10 μM naloxone. For data analysis, the radioactivitycounts were normalized to values where 100% represents effect of bufferand 0% represents non-specific binding. Five independent experiments,each done in quadruplicate, were performed and the resulting values werecalculated and pooled to a mean curve which is displayed.

GTPγS Binding Experiments:

The [³⁵S]-GTPγS binding assay was performed with membrane preparationsfrom HEK 293 cells coexpressing the human μOR and the PTX insensitiveG-protein subunits Gα_(o1) or Gα_(i2). Cells were transientlytransfected using the Mirus TransIT-293 transfection reagent (MoBiTec,Goettingen, Germany), grown for 48 hrs, harvested and homogenates wereprepared as described. The receptor expression level (B_(max)) and K_(D)values were determined in saturation experiments with ³H-diprenorphine(specific activity: 30 Ci/mmol, purchased from Biotrend, Cologne,Germany) (B_(max)=3700±980 fmol/mg protein, K_(D)=0.30±0.093 nM forμOR+Gα_(o1) or B_(max)=5800±2000 fmol/mg, K_(D)=0.46±0.095 nM forμOR+Gα_(i2), respectively). The assay was carried out in 96-well plateswith a final volume of 200 μL. In each well, 10 μM GDP, the compounds(0.1 pM to 100 μM final concentration) and the membranes (30 μg/mL finalprotein concentration) were incubated for 30 min at 37° C. in incubationbuffer containing 20 mM HEPES, 10 mM MgCl₂.6 H₂O and 70 mg/L saponin.After the addition of 0.1 nM [³⁵S]-GTPγS (specific activity 1250Ci/mmol, PerkinElmer, Rodgau, Germany) incubation was continued at 37°C. for further 30 min or 75 min for μOR+Gα_(o1) or μOR+Gα_(i2),respectively. Incubation was stopped by filtration through Whatman GF/Bfilters soaked with ice cold PBS. Bound radioactivity was measured byscintillation measurement as described previously.

Data analysis was performed by normalizing the radioactivity counts(ccpms) to values when 0% represents the non-stimulated receptor and100% the maximum effect of morphine or DAMGO. Dose-response curves werecalculated by non-linear regression in GraphPad Prism 6.0. Mean values±S.E.M. for EC₅₀ and E_(max) values were derived from 3-12 individualexperiments each done in triplicate.

G_(i/o) Induced cAMP Inhibition:

To measure μOR G_(i/o)-mediated cAMP inhibition, HEK293T cells wereco-transfected using calcium phosphate in a 1:1 ratio with human μOR anda split-luciferase based cAMP biosensor (pGloSensor™-22F; Promega). Forexperiments including GRK2 co-expression, cells were transfected with 1μg/15-cm dish of GRK2. After at least 24 hours, transfected cells werewashed with phosphate buffered saline (PBS) and trypsin was used todissociate the cells. Cells were centrifuged, resuspended in platingmedia (1% dialyzed FBS in DMEM), plated at a density of 15,000-20,000cells per 40 μl per well in poly-lysine coated 384-well white clearbottom cell culture plates, and incubated at 37° C. with 5% CO₂overnight. For inactivation of pertussis-toxin (PTX) Gα_(i/o)experiments, cells were plated with 100 ng/mL final concentration PTX.The next day, drug dilutions were prepared in fresh assay buffer (20 mMHEPES, 1×HBSS, 0.1% bovine serum album (BSA), and 0.01% ascorbic acid,pH 7.4) at 3× drug concentration. Plates were decanted and 20 μL perwell of drug buffer (20 mM HEPES, 1×HBSS, pH 7.4) was added to eachwell. Drug addition to 384 well plates was performed by FLIPR adding 10uL of drug per well for a total volume of 30 μL. Plates were allowed toincubate for exactly 15 minutes in the dark at room temperature. Tostimulate endogenous cAMP via β adrenergic-G_(s) activation, 10 μL of 4×isoproterenol (200 nM final concentration) diluted in drug buffersupplemented with GloSensor assay substrate was added per well. Cellswere again incubated in the dark at room temperature for 15 minutes, andluminescence intensity was quantified using a Wallac TriLux microbeta(Perkin Elmer) luminescence counter. Data were normalized toDAMGO-induced cAMP inhibition and analyzed using nonlinear regression inGraphPad Prism 6.0 (Graphpad Software Inc., San Diego, Calif.).

Determination of functional activity of PZM21-29 for SAR studies wasperformed using a BRET-based cAMP accumulation assay. HEK-293T cellswere transiently co-transfected with pcDNA3L-His-CAMYEL42 (purchasedfrom ATCC via LCG Standards, Wesel, Germany) and human μOR a cDNA ratioof 2:2 using Mirus TransIT-293 transfection reagent. 24 hourspost-transfection, cells were seeded into white half-area 96-well platesat 20×10⁴ cells/well and grown overnight. On the following day, phenolred free medium was removed and replaced by Phosphate Buffered Saline(PBS) and cells were serum starved for 1 hour before treatment. Theassay was started by adding 10 μL coelenterazine h (Progmega, Mannheim,Germany) to each well to yield a final concentration of 5 μM. After 5minute incubation, compounds were added in PBS containing forskolin(final concentration 10 μM). Reads of the plates started 15 minutesafter agonist addition. BRET readings were collected using a CLARIOstarplate reader (BMG LabTech, Ortenberg, Germany). Emission signals fromRenilla Luciferase and YFP were measured simultaneously using a BRET1filter set (475-30 nm/535-30 nm). BRET ratios (emission at 535-30nm/emission at 475-30 nm) were calculated and dose-response curves werefitted by nonlinear regression using GraphPad Prism 6.0. Curves werenormalized to basal BRET ratio obtained from dPBS and the maximum effectof morphine and DAMGO. Each curve is derived from three to fiveindependent experiments each done in duplicate.

Calcium Release:

Calcium release was measured using a FLIPR^(TETRA) fluorescence imagingplate reader (Molecular Devices). Calcium release experiments were runin parallel to Gi/o Glosensor experiments with the same HEKT cellstransfected with μOR, except cells for FLIPR were plated in poly-lysinecoated 384-well black clear bottom cell culture plates. Cells wereincubated at 37° C. with 5% CO₂ overnight, and next day, media wasdecanted and replaced with Fluo-4 direct calcium dye (Life Technologies)made up in HBSS with 20 mM HEPES, pH 7.4. Dye was incubated for 1 hourat 37° C. Afterwards, cells were equilibrated to room temperature, andfluorescence in each well was read for the initial 10 seconds toestablish a baseline. Afterwards, 10 μL of drug (3X) was added per welland the maximum-fold increase in fluorescence was determined asfold-over-baseline. Drug solutions used for the FLIPR assay were exactlythe same as used for Gi/o Glosensor experiments. To activate endogenousG_(q)-coupled receptors as a positive control for calcium release,TFLLR-NH₂ (10 μM, PAR-1 selective agonist) was used.

Receptor Internalization:

Internalization was measured using the eXpress DiscoveRx PathHunter GPCRinternalization assay utilizing split β-galactosidase complementation.Briefly, cryopreserved U2OS cells expressing the human μOR were thawedrapidly and plated in supplied medium and 96-well culture plates. Nextday, cells were stimulated with drugs (10×) and allowed to incubate for90 minutes at 37° C. with 5% CO₂. Afterwards, substrate was added tocells and chemiluminescence was measured on a TriLux (Perkin Elmer)plate counter. Data were normalized to DAMGO and analyzed using GraphpadPrism 6.0.

β-Arrestin Recruitment Assays:

β-Arrestin recruitment was measured by either the PathHunter enzymecomplementation assay (DiscoveRx) or by previously describedbioluminescence resonance energy transfer (BRET) methods. Assays usingDiscoveRx PathHunter eXpress OPRM1 CHO-K1 Beta-Arrestin GPCR Assays wereconducted exactly as instructed by the manufacturer. Briefly, suppliedcryopreserved cells were thawed and resuspended in the supplied medium,and plated in the furnished 96-well plates. Next day, 10× dilutions ofagonist (prepared in HBSS and 20 mM HEPES, pH 7.4) were added to thecells and incubated for 90 minutes. Next, the detection reagents werereconstituted, mixed at the appropriate ratio, and added to the cells.After 60 min, luminescence per well was measured on a TriLux(Perkin-Elmer) plate counter. Data were normalized to DAMGO and analyzedusing the sigmoidal dose-response function built into GraphPad Prism6.0.

To measure μOR mediated β-Arrestin recruitment by BRET in the presenceor absence of GRK2 co-expression, HEK293T cells were co-transfected in a1:1:15 ratio with human μOR containing C-terminal renilla luciferase(RLuc8), GRK2, and Venus-tagged N-terminal β-arrestin2, respectively. Inthe case of experiments where GRK2 expression was varied, pcDNA3.1 wassubstituted for GRK2 to maintain the same concentration of DNAtransfected. After at least 24 hours, transfected cells were plated inpoly-lysine coated 96-well white clear bottom cell culture plates inplating media at a density of 125,000-250,000 cells per 200 μl per welland incubated overnight. The next day, media was decanted and cells werewashed twice with 60 μL of drug buffer and incubated at room temperaturefor at least 10 minutes prior to drug stimulation. 30 μL of drug (3X)was added per well and incubated for at least 30 minutes in the dark.Then, 10 μL of the RLuc substrate, coelenterazine H (Promega, 5 μM finalconcentration) was added per well, and plates were read for bothluminescence at 485 nm and fluorescent eYFP emission at 530 nm for 1second per well using a Mithras LB940 microplate reader. The ratio ofeYFP/RLuc was calculated per well and the net BRET ratio was calculatedby substracting the eYFP/RLuc per well from the eYFP/RLuc ratio withoutVenus-Arrestin present. Data were normalized to DAMGO-inducedstimulation and analyzed using nonlinear regression in GraphPad Prism6.0.

Ligand Bias Calculation:

Multiple approaches have been described to quantitate ligand bias,including operational models, intrinsic relative activity models, andallosteric models. In the absence of GRK2, we observe no β-arrestin2recruitment for PZM21 and TRV130. This prevents a quantitativeassessment of bias by the operational model. In the case where GRK2 isoverexpressed, we observe arrestin recruitment for PZM21 and TRV130. Inthis case, we utilize the operational model to calculate ligand bias anddisplay equiactive bias plots for comparison of ligand efficacy fordistinct signaling pathways. The Glosensor G_(i/o), DiscoverX PathHunterβ-arrestin, or net BRET concentration response curves were fit to theBlack-Leff operational model to determine transduction coefficients(_(T)/K_(A)). Compound bias factors are expressed after normalizationagainst the prototypical opioid agonist DAMGO used as a reference. Biasfactors are expressed as the value of ΔΔ log(_(T)/K_(A)).

Assessment of Off-Target PZM21 Activity:

To identify potential off-target activity of PZM21, we utilized theNational Institutes of Mental Health Psychoactive Drug Screen Program.Compound PZM21 was first tested for activity against 320 non-olfactoryGPCRs using the PRESTO-Tango GPCRome screening β-arrestin recruitmentassay. We used 10 μM PZM21 and activity at each receptor was measured inquadruplicate. Potential positive receptor hits were defined as thosethat increase the relative luminescence value by two fold. Positive hitswere subsequently re-tested in full dose-response mode to determinewhether the luminescence signal titrates with increasing concentrationsof PZM21. A number of false positive hits were discounted by thisapproach. PZM21 inhibition of hERG channel was performed as describedpreviously⁵⁵ and neurotransmitter transporter assays were determinedused the Molecular Devices Neurotransmitter Assay Kit (MolecularDevices).

In Vivo Studies:

Adult male C57BL/6J obtained from Jackson Laboratories (Bar Harbor, Me.)were used to investigate behavioral responses, respiratory effects, andhyperlocomotion induced by PZM21 and compared with morphine or vehicle(0.9% sodium chloride). For μOR knockout animals, Oprm1−/− mice(B6.129S2-Oprm1tm1Kff/J) were obtained from Jackson Laboratories. Alldrugs were dissolved in vehicle and injected subcutaneously. Each studyincorporated more than 7 mice. Behavioral studies were conducted at theUniversity of North Carolina following the National Institutes ofHealth's guidelines for care and use of animals and with approved mouseprotocols from the institutional animal care and use committees.

Measurement of Analgesia:

Analgesia-like responses in were measured as previously described usinga hotplate analgesia meter with dimensions of 29.2×26.7 cm with micerestricted to a cylinder 8.9 cm in diameter and 15.2 cm high (IITC LifeSciences, Woodland Hills, Calif.). Response was measured by recordingthe latency to lick, flutter, or splay hind paw(s), or an attempt tojump out of the apparatus at 55° C., with a maximum cutoff time of 30 s.Once a response was observed or the cutoff time had elapsed, the subjectwas immediately removed from the hotplate and placed back in its homecage. The animals were acclimated to the hotplate, while cool, and abaseline analgesic response time was acquired several hours before drugtreatment and testing. Mice were injected with either vehicle, morphine(5 mg/kg or 10 mg/kg), TRV130 (1.2 mg/kg) or PZM21 (10 mg/kg, 20 mg/kg,or 40 mg/kg). After injection of drug, the analgesic effect expressed aspercentage maximum possible effect (% MPE) was measured at 15, 30, 60,90, and 120 minutes after drug treatment. If animals did not displayhind paw lick, splay, or flutter, they were removed from the trial.Additionally, if animals attempted to jump out of the plate or urinatedon the hotplate they were removed from the trial. To assess analgesia bythe tail-flick assay, a tail flick analgesia meter (ColumbusInstruments, Columbus, Ohio). Mice were gently immobilized with a cottontowel and the tail base was placed on a radiant light source emitting aconstant temperature of 56° C. The tail withdrawal latency was measuredat similar time points as the hot-plate assay after administration ofvehicle, morphine or PZM21. The cutoff time for the heat source was setat 10 seconds to avoid tissue damage. Analgesic response times weremeasured similar to the hot plate assay.

Analgesia in μOR knockout mice and subcategorization ofaffective/reflexive pain: Oprm1−/− and wild-type C57Bl/6J mice (male;8-11 weeks) were acclimated to the testing environment and thermal-plateequipment for three non-consecutive days between 11 A.M. and 1 P.M.prior to any pharmacological studies. Acclimation was achieved byindividually confining mice within an enclosed semi-transparent redplastic cylinder (10 cm D×15 cm H) on a raised metal-mesh rack (61 cm H)for 30 minutes, and then exposing each mouse to the thermal-plateequipment (non-heated; floor dimensions, 16.5×16.5 cm; Bioseb), whileconfined within a clear plastic chamber (16 L×16 W×30 H cm). Acclimationexposure to the thermal plate lasted for 30 seconds, and exposure wasrepeated after 30 minutes to mimic the test day conditions. The testingenvironment had an average ambient temperature of 22.6° C. andillumination of 309 lux from overhead fluorescence lighting. The samemale experimenter (G.C.) was present throughout the entire duration ofhabituation and testing to exclude possible olfaction-inducedalterations in sensory thresholds.

Cutaneous application of a noxious stimulus, or time spent on a hotplate apparatus can broadly elicit several distinct behavioralresponses: 1. Withdrawal reflexes: rapid reflexive retraction or digitsplaying of the paw, 2. Affective-motivational responses: directedlicking and biting of the paw, and/or a motivational responsecharacterized by jumping away from the heated floor plate. Pawwithdrawal reflexes are classically measured in studies ofhypersensitivity, and involve simple spinal cord and brainstem circuits.In contrast, affective responses are complex, non-stereotyped behaviorsrequiring processing by limbic and cortical circuits in the brain, theappearance of which indicates the subject's motivation and arousal tomake the unpleasant sensation cease by licking the affected tissue, orseeking an escape route. To distinguish between potential differentialanalgesic effects of PZM21, mice were placed on the heated apparatus(52.5° C.), and the latency to exhibition of the first sign of a hindpawreflexive withdraw, and the first sign of an affective response wasrecorded. A maximum exposure cutoff of 30 seconds was set to reducetissue damage. Mice were injected with either vehicle, morphine (10mg/kg), or PZM21 (20 mg/kg). After injection of drug, the analgesiceffect on either reflex or attending responses was expressed aspercentage maximum possible effect (% MPE), and was measured at −30(baseline), 15, 30, 60, 90, 120, and 180 minutes relative to drugtreatment.

Formalin Injection Assay:

Analgesia to formalin injection was carried out as describedpreviously⁶⁶. Mice were first habituated for 20 minutes to the testingenvironment which included a home cage without bedding, food, and water.After habituation, vehicle, morphine (10 mg/kg), or PZM21 (40 mg/kg) wasinjected subcutaneously. This was followed by injection of 20 μL of 1%formalin in 0.9% saline under the skin of the dorsal surface of theright hindpaw. Animals were returned to their home cage and behavioralresponses were recorded for one hour. Nociception was estimated bymeasuring the cumulative time spent by animals licking theformalin-injected paw. As opioids classically display two phases ofanalgesic action, nociceptive behavior was measured during both theearly phase (0 to 5 minutes) and the late phase (20 to 30 minutes).

Mouse Plethysmography:

Respiration data was collected using a whole body plethysmography system(Buxco Electronics Inc, Wilmington, N.C.) as described⁶⁷. This methodmeasures respiratory frequency, tidal volume, peak flows, inspiratorytime, and expiratory time in conscious and unrestrained mice. Briefly,Buxco airflow transducers were attached to each plethysmography chamberand a constant flow rate was maintained for all chambers. Each chamberwas calibrated to its attached transducer prior to the experiment.Animals were first habituated to the clear plexiglass chambers for 10minutes. Respiratory parameters were recorded for 10 minutes toestablish a baseline prior to injection of vehicle, morphine (10 mg/kg),TRV130 (1.2 mg/kg) or PZM21 (20 mg/kg or 40 mg/kg). Respiratoryparameters were then collected on unrestrained mice for 100 minutes postdrug injection. To decrease respiratory variability induced by anxiety,mice were shielded from view of other animals and experimenter.

Accumulated Fecal Boli Quantification:

To measure constipatory effects of morphine and PZM21, we assessed thetotal accumulated fecal boli as described previously. Briefly, mice wereinjected with vehicle, morphine (10 mg/kg) or PZM21 (20 mg/kg) andplaced within a plexiglass chamber (5 cm×8 cm×8 cm) positioned on a meshscreen. Mice were maintained without food or water for 6 hours. Fecalboli were collected underneath the mesh on a paper towel and thecumulative mass was measured every hour for six hours.

Open Field Locomotor Response:

A photocell-equipped automated open field chamber (40 cm×40 cm×30 cm;Versamax system, Accuscan Instruments) contained insidesound-attenuating boxes was used to assess locomotor activity. Baselineambulation of freely moving mice was monitored over 30 minutes, followedby injection with vehicle, morphine (10 mg/kg) or PZM21 (20 mg/kg).Locomotor activity was monitored for another 150 minutes.

Conditioned Place Preference:

A three-chambered conditioned place preference apparatus(Med-Associates, St. Albans, Vt.) consisting of white or black chambers(16.8×12.7×12.7 cm each) with uniquely textured white mesh or black rodfloors and separated by a neutral central chamber (7.2×12.7×12.7 cm) wasused for conditioned place preference testing. On day 1 (preconditioningday), mice were placed in the central chamber and allowed to explorefreely for 30 minutes. Time spent in each compartment was used toestimate baseline chamber preferences and mice showing specific chamberbias more than 70% were not studied further. On days 2-9 (conditioningdays) mice were injected with either vehicle or drug and paired witheither the white mesh or the black rod chambers. All mice receivedvehicle on days 2, 4, 6, 8 and drug on days 3, 5, 7, 9. On day 10 (testday), mice were again placed in the central chamber as on day 1 andallowed to explore freely for 30 minutes. Time spent in each chamber wasexpressed as percentage preference.

Cataleptic Effect:

Drug induced catalepsy was measured in mice using the bar test, whichincludes a horizontally placed 3 mm diameter wooden bar fixed 4 cm abovethe floor. Mice were habituated with the bar and the environment for 20minutes before subcutaneous injection of either haloperidol (2 mg/kg),morphine (10 mg/kg), or PZM21 (20 mg/kg). To measure catalepsy, bothforepaws were gently placed on the bar and the length of time duringwhich each mouse remained in the initial position was measured. Theeffect was measured at 15, 30 and 90 minutes after drug injection.Maximum cut-off time for each challenge was 90 seconds.

Pharmacokinetics of PZM21:

Studies were performed by the Preclinical Therapeutics Core and the DrugStudies Unit at the University of California San Francisco. Ten micewere injected subcutaneously with 20 mg/kg of PZM21. At each time point,1 mL of blood was collected from three mice and the serum concentrationof PZM21 determined by liquid chromatography-mass spectrometry (LC/MS).Mice were subsequently sacrificed and entire brains were homogenized fordetermination of PZM21 concentrations by LC/MS. All studies wereperformed with approved mouse protocols from the institutional animalcare and use committees.

Metabolism of PZM21:

Metabolism experiments were performed as described previously. In brief,pooled microsomes from male mouse liver (CD-1) were purchased (SigmaAldrich) and stored at −75° C. until required. NADPH was purchased (CarlRoth) and stored at −8° C. The incubation reactions were carried out inpolyethylene caps (Eppendorf, 1.5 mL) at 37° C. The incubation mixturecontained PZM21 (80 μM) or positive controls (imipramine androtigotine), pooled liver microsomes (0.5 mg of microsomal protein/mL ofincubation mixture) and Tris-MgCl₂ buffer (48 mM Tris, 4.8 mM MgCl₂, pH7.4). The final incubation volume was 0.5 mL. Microsomal reactions wereinitiated by addition of 50 μL of enzyme cofactor solution NADPH (finalconcentration of 1 mM). At 0, 15, 30 and 60 min the enzymatic reactionswere terminated by addition of 500 μL of ice-cold acetonitrile(containing 8 μM internal standard), and precipitated protein wasremoved by centrifugation (15,000 rcf for 3 min). The supernatant wasanalyzed by HPLC/MS (binary solvent system, eluent acetonitrile in 0.1%aqueous formic acid, 10-40% acetonitrile in 8 min, 40-95% acetonitrilein 1 min, 95% acetonitrile for 1 min, flow rate of 0.3 mL/min). Theexperiments were repeated in three independent experiments. Parallelcontrol incubations were conducted in the absence of cofactor solutionto determine unspecific binding to matrix. Substrate remaining andmetabolite formation was calculated as a mean value ±SEM of threeindependent experiments by comparing AUC of metabolites and substrateafter predetermined incubation time to AUC of substrate at time 0,estimating a similar ionization rate, corrected by a factor calculatedfrom the AUC of internal standard at each time point.

Chemical Synthesis:

The stereochemically pure isomers of 12 and PZM21 were synthesized fromcorresponding (R)- and (S)-amino acid amides, which were eithercommercially available or readily prepared from the corresponding acidor ester (see Example 2). The primary amino group was dimethylated usingan excess of aqueous formaldehyde and sodium triacetoxyborohydride inaqueous acetonitrile. The carboxamides 16a,b were converted to primaryamines by treatment with borane-tetrahydrofurane complex under refluxyielding the diamines 17a,b. Henry reaction of thiophene-3-carbaldehydewith nitroethane afforded the nitropropene derivative 18, which wasconverted into the racemic alkylamine 19. Activation with 4-nitrophenylchloroformate yielded the carbamates 20, which were coupled with theenantiopure primary amines 17a,b to achieve diastereomeric mixtures ofthe corresponding ureas 12 and 21. HPLC separation using asemi-preparative Chiralpak AS-H column gave the overall eight purestereoisomers of 12 and 21 including PZM21.

To determine the absolute configuration of the final products andefficiently prepare PZM21, we synthesized enantiomerically enrichedcarbamate 20, coupled it with the corresponding primary amines. Forenantiomeric enrichment, we performed chiral resolution of the racemicprimary amine 19 via repetitive crystallization withdi-p-anisoyl-(S)-tartaric acid. After triple crystallization, weobtained 19 enriched in dextrorotatory enantiomer ([α]_(D) ²⁵=+20.5 0).The corresponding (R)-acetamide has been previously characterized asdextrorotatory ([α]_(D) ²⁰=+49.8°), so enantiomerically enriched 19 wastreated with acetic anhydride and triethylamine, and the specificrotation of the product was measured. Based on the value of specificrotation of the resulting acetamide ([α]_(D) ²¹=−46.6°), we assigned theabsolute configuration of the major isomer to be (S). (S)-enriched 20was used for synthesis of the final urea derivatives and absoluteconfiguration of diastereomers in pairs was assigned based on theequality of retention time in chiral HPLC. A full description of thesynthetic routes and analytical data of the compounds 12, PZM21 and itsanalogs PZM22-29 are presented in Example 2.

Detailed Modeling of PZM21 and TRV130 Binding Poses:

PZM21 was docked to the inactive state μOR structure using DOCK3.6 asdescribed for the primary screen, with the exception that the forty-fivematching spheres used were generated based on the docked pose ofcompound 12. The resulting ligand-receptor complex was further optimizedthrough minimization with the AMBER protein force field and the GAFFligand force field supplemented with AM1-BCC charges. Docking of PZM21and TRV130 to the active state OR structure (PDB: 5C1M) was alsoperformed with DOCK3.6 with parameters as described above. Theamino-terminus of the active state OR, which forms a lid over theorthosteric binding site (residues Gly52-Met65) was removed prior toreceptor preparation. Matching spheres were generated based on the poseof PZM21 in the inactive state. The resulting complexes were thenminimized with AMBER. PZM21's pose in the active state μOR structure wasfurther refined using Glide (Schrödinger) in XP mode.

Molecular dynamics simulations were based on crystal structures of μORin the inactive-and active-state conformation (PDB: 4DKL and 5CM1,respectively). In both cases, all non-receptor residues (T4 lysozyme inthe inactive state and Nb39 in the active state) were removed. For theactive state, amino-terminal residues were removed as for dockingstudies above. Initial coordinates of PZM21 were generated by moleculardocking as described above. The receptor was simulated with twotautomers of His297^(6.52), either in the neutral Ndelta or the Neplisonstate. The μOR-PZM21 complex was embedded in a lipid bilayer consistingof dioleoylphosphatidylcholine (DOPC) molecules as described previously.The charges of the inactive- and active-state simulation systems wereneutralized by adding 11 and 14 chloride ions, respectively. To carryout MD simulations, the GROMACS simulation package was used as describedpreviously. Briefly, the general AMBER force field (GAFF) was used forPZM21 and the lipids and the AMBER force field ff99SB for the receptor.Parameters for PZM21 were assigned using antechamber, and charges werecalculated using Gaussian09 (Gaussian, Inc.) at the HF/6-31(d,p) leveland the RESP procedure according to the literature. During thesimulations, PZM21 was protonated at its tertiary amine and simulated asa cation. The SPC/E water model was used, and the simulations werecarried out at 310 K. Analysis of the trajectories was performed usingthe GROMACS simulation package. Each simulation in a given condition wasinitiated from identical coordinates, but with initial atom velocitiesassigned independently and randomly. An overview of the simulationsystems and their simulation times is shown in Example 2.

TABLE 4 Receptor binding and activation data—opioid receptor ligandshMOR + G_(qi5) humanDOR hKOR hMOR IP accumulation compound[3H]dyprenorphine [3H]dyprenorphine [3H]dyprenorphine assay phenylsubstituted ligands

  BD 127 DR

  BD 127 DS BD 127DR (2) 12000 ± 15000 (2) 5000 ± 2700 (2) 2900 ± 150033446 BD 127DS (2) 11000 ± 8800 (2) 3100 ± 280 (2) 2400 ± 2000 33445

  BD 127 LR

  BD 127 LS (S,S)-12 120 nM MOR agonist BD 127LR (3) 1800 ± 150 (3) 1300± 300 (3) 380 ± 96 33448 BD 127LS (2) 2800 ± 1800 (2) 1000 ± 520 (2) 140± 84 33447 4-hydroxyphenyl substituted ligands (23)

  DD 16 58 nM MOR agonist DD 16 (3) 330 ± 160 (3) 150 ± 35 (6) 43 ± 11

  BD 122 DR

  BD 122 DS BD 122DR (2) 4100 ± 2200 (2) 3100 ± 280 (2) 290 ± 150 33175BD 122DS (2) 4800 ± 3300 (2) 2300 ± 2300 (2) 480 ± 57 33176

  BD 122 LR

  BD 122 LS (S,S)-21 BD 122LR (4) 88 ± 16 (4) 190 ± 23 (4) 42 ± 11 (2)EC₅₀: 47 nM 33444 a: 17% BD 122LS (3) 470 ± 98 (3) 33 ± 5.6 (3) 36 ± 8.2(3) EC₅₀: 37 nM 33443 a: 73%

  DD 61L-A

  DD 61L-B DD 61L-A (2) 91 ± 28 (2) 67 ± 23 (2) 81 ± 18 DD 61L-B (2) 360± 64 (2) 37 ± 26 (2) 42 ± 5.0

  DD 63LR

  DD 63LS DD 63L-RS (2) 44 ± 1.4 (2) 14 ± 0.71 (2) 16 ± 1.4diastereomeric mixture

  DD 53 LS

  DD 51 LS DD 53LS (2) 180 ± 71 (2) 22 ± 13 (2) 28 ± 18 DD 51LS (3) 700± 150 (3) 180 ± 47 (3) 150 ± 11

  DD 50 LS

  DD 57L DD 50LS (3) 570 ± 270 (3) 71 ± 17 (3) 84 ± 20 DD 57L (2) 74 ±51 (2) 40 ± 9.2 (2) 8.3 ± 3.8

  DD 32L

  DD 33L DD 32L (4) 650 ± 130 (4) 46 ± 5.3 (4) 38 ± 8.9 DD 33L (3) 920 ±240 (3) 91 ± 14 (3) 46 ± 11 3-hydroxyphenyl substituted ligands

  DD 47 LS

  DD 46L DD 47LS (4) 350 ± 78 (4) 46 ± 6.7 (4) 34 ± 2.2 DD 46L (3) 190 ±12 (3) 32 ± 4.3 (3) 25 ± 9.0 2,6-dimethyl-4-hydroxyphenyl substitutedligands

  DD 34L DD 34L (3) 51 ± 4.8 (3) 27 ± 3.2 (3) 6.2 ± 0.85 (2) EC₅₀: — nMa: <5% (22)

  BD 131 LR

  BD 131 LS BD 131LR (4) 17 ± 6.5 (4) 12 ± 0.90 (4) 4.1 ± 0.97 (2) EC₅₀:— nM @ 10 μM a: 10% BD 131LS (3) 85 ± 30 (3) 6.5 ± 2.1 (3) 12 ± 1.7 (2)EC₅₀: — nM a: <5% hydroxypyridyl substituted ligands

  DD xxy

  DD xxz DD xxy DD xxz

K_(i) values [nM±SD] for two individual experiments or K_(i) in [nM±SEM]derived from (n) independent experiments all done in triplicate. EC₅₀[nM] and efficacy a [% morphine] from combined curves derived from IPaccumulation experiments (n) in triplicate.

TABLE 5A Compound Assay DAMGO PZM21 DD90 DD184 DD108 DD102 DD109 DD63L-BDD61L-B Arrestin EC50 nM 353 91.96 53.46 No Activity 4713 1984 NoActivity 397.2 84.09 Arrestin pEC50 6.45 7.036 7.272 N/D 5.327 5.703 N/D6.401 7.075 Arrestin pEC50 SEM 0.05 0.1901 0.3081 N/D 0.05503 0.1039 N/D0.09686 0.187 Arrestin Emax % DAMGO 100 15 5 No Activity 120 30 NoActivity 38 12 Arrestin Emax SEM 2.8 1.307 0.6839 N/D 6.78 2.483 N/D2.034 0.9993 Arrestin + GRK2 EC50 nM 42 107.5 144.3 No Activity 14911499 No Activity 82.06 278.1 Arrestin + GRK2 pEC50 7.37 6.969 6.841 N/D5.826 5.824 N/D 7.086 6.556 Arrestin + GRK2 pEC50 SEM 0.04 0.062720.09356 N/D 0.02826 0.06056 N/D 0.04359 0.06909 Arrestin + GRK2 Emax %100 76 31 No Activity 118 61 No Activity 92 79 DAMGO Arrestin + GRK2Emax SEM 1.7 2.205 1.404 N/D 2.441 2.711 N/D 2.1 2.874 Gi/o EC50 nM 3.1610.12 4.252 558.6 35.07 37.93 No Activity 5.697 35.46 Gi/o pEC50 8.507.995 8.371 6.253 7.455 7.421 N/D 8.244 7.45 Gi/o pEC50 SEM 0.09 0.15180.09051 0.3179 0.1215 0.1012 N/D 0.06386 0.1509 Gi/o Emax % DAMGO 100 7476 40 86 76 No Activity 88 84 Gi/o Emax SEM 2.9 4.178 2.392 7.081 4.2923.203 N/D 1.995 4.56 N/D: Not Determined

TABLE 5B Cmpd No. Assay DD88B DD47 LS DD131 DD16 DD32L DD33L DD81 DD53LSDD57L Arrestin EC50 nM 15.48 357.5 229.7 410 5.227 No Activity 24.9167.92 No Activity Arrestin pEC50 7.81 6.447 6.639 6.387 8.282 N/D 7.6047.168 N/D Arrestin pEC50 SEM 0.3934 0.1681 0.1864 0.3349 0.7404 N/D0.4664 0.3609 N/D Arrestin Emax % DAMGO 5 12 11 5 3 No Activity 3 5 NoActivity Arrestin Emax SEM 0.754 1.059 1.03 1.016 0.6845 N/D 0.52250.8031 N/D Arrestin + GRK2 EC50 nM 100.8 210.9 213.4 143.6 49.39 133.767.07 87.36 No Activity Arrestin + GRK2 pEC50 6.997 6.676 6.671 6.8437.306 6.874 7.173 7.059 N/D Arrestin + GRK2 pEC50 SEM 0.09398 0.076380.0846 0.09999 0.1503 0.1712 0.1367 0.09247 N/D Arrestin + GRK2 Emax %45 70 45 33 24 14 27 33 No Activity DAMGO Arrestin + GRK2 Emax SEM 1.942.714 1.932 1.598 1.522 1.152 1.636 1.359 N/D Gi/o EC50 nM 9.239 16.987.94 7.554 23.49 98.06 15.11 3.078 No Activity Gi/o pEC50 8.034 7.77 8.18.122 7.629 7.008 7.821 8.512 N/D Gi/o pEC50 SEM 0.1238 0.1336 0.19180.1493 0.1864 0.2297 0.4286 0.1265 N/D Gi/o Emax % DAMGO 67 73 57 60 5261 22 63 No Activity Gi/o Emax SEM 3.062 3.768 3.987 3.222 3.831 5.5693.508 2.715 N/D N/D: Not Determined

TABLE 5C Ligands for Table 5A and 5B. DAMGO

PZM21

DD 90

DD 184

DD 108

DD 102

DD 109

DD 63L-B

DD 61L-B

DD 88B

DD 47 LS

DD 131

DD 16

DD 32L

DD 33L

DD 81

DD 53 LS

DD 57L

Example 4. Additional Characterization and Syntheses Method A: GeneralMethod for Synthesis of Urea Compounds

Compound 35 (R²═OH, R³═R═CH₃, R⁴═H, X═Y═C) [or (R)-17a (R²═H, R³═R⁵═CH₃,R⁴═H, X═Y═C)/(S)-17a (R²═H, R³═R⁵═CH₃, R⁴═H, X═Y═C)/(R)-17b (R²═OH,R³═R⁵═CH₃, R⁴═H, X═Y═C), (S)-DD45 (R²═H, R³═R⁵═CH₃, R⁴═OH, X═Y═C),(S)-DD74 (R³═R⁵═CH₃, R⁴═OH, X═C, Y═N), (S)-DD76 (R²═OH, R³═R⁵═CH₃, R⁴═H,X═N, Y═C), (S)-DD122((S)-3-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-N²,N²-dimethylpropane-1,2-diamine),(S)-DDLM18 ((S)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-N²,N²-dimethylpropane-1,2-diamine), (S)-DDLM12((S)-4-(3-amino-2-(pyrrolidin-1-yl)propyl)phenol), (S)-DD195 (R²═OH,R³═H, R═CH₃, R⁴═H, X═Y═C), 36 (R²═OH, R³=Bn, R⁵═CH₃, R⁴═H, X═Y═C),(S)-DD199 (R²═OH, R³═H, R⁵=Fmoc, R⁴═H, X═Y═C)] (1.2 eq) was suspended indry DMF in a microwave tube. Triethylamine (0.6 eq) and4-nitrophenyl-R¹-carbamate (1 eq) were added and the mixture was stirredat room temperature under argon atmosphere for 3-20 hours. Then, thesolution was diluted with isopropanol/EtOAc (1:3) and washed with asaturated aqueous solution of NaHCO₃. The organic layer was extractedwith 0.1N HCl-solution and the aqueous extracts were adjusted to pH 9with saturated aqueous NaHCO₃/Na₂CO₃ solution and finally extracted withEtOAc. The organic layers were dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The residue was purified by preparative HPLCgiving the corresponding formates or trifluoroacetates.

Compounds Synthesized Following Method A(S)-1-(2-(dimethylamino)-3-phenylpropyl)-3-(2-(thiophen-3-yl)ethyl)urea(DD18)

Yield: 42%. LCMS (ESI+): t_(R)=14.0-14.3 min, m/z found 332.7, m/z calcd332.2 [M+H]⁺.

(R)-1-(2-(dimethylamino)-3-phenylpropyl)-3-(2-(thiophen-3-yl)ethyl)urea(DD17)

Yield: 56%. LCMS (ESI+): t_(R)=14.6-15.4 min, m/z found 332.8, m/z calcd332.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-(thiophen-3-yl)ethyl)urea(DD16)

Yield: 40%. LCMS (ESI+): t_(R)=14.0-14.3 min, m/z found 348.8, m/z calcd348.2 [M+H]⁺.

(R)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-(thiophen-3-yl)ethyl)urea(DD15)

Yield: 47%. LCMS (ESI+): t_(R)=13.3-14.2 min, m/z found 348.7, m/z calcd348.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-methyl-1-(thiophen-3-yl)propan-2-yl)urea(DD32L)

Yield: 50%. LCMS (ESI+): t_(R)=9.5-9.8 min, m/z found 376.7, m/z calcd376.2 [M+H]⁺.

(R)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-methyl-1-(thiophen-3-yl)propan-2-yl)urea(DD32D)

Yield: 54%. LCMS (ESI+): t_(R)=1.2-15.8 min, m/z found 376.7, m/z calcd376.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-phenylpropyl)-3-(2-methyl-1-(thiophen-3-yl)propan-2-yl)urea(DD35L)

Yield: 56%. LCMS (ESI+): t_(R)=15.1-16.8 min, m/z found 360.7, m/z calcd360.2 [M+H]⁺

(R)-1-(2-(dimethylamino)-3-phenylpropyl)-3-(2-methyl-1-(thiophen-3-yl)propan-2-yl)urea(DD35D)

Yield: 45%. LCMS (ESI+): t_(R)=15.2-17.0 min, m/z found 360.8, m/z calcd360.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-methyl-1-phenylpropan-2-yl)urea(DD33L)

Yield: 27%. LCMS (ESI+): t_(R)=15.2-16.0 min, m/z found 370.8, m/z calcd370.2 [M+H]⁺.

(R)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-methyl-1-phenylpropan-2-yl)urea(DD33D)

Yield: 17%. LCMS (ESI+): t_(R)=13.6-14.8 min, m/z found 370.8, m/z calcd370.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-phenylpropyl)-3-(2-methyl-1-phenylpropan-2-yl)urea(DD36L)

Yield: 48%. LCMS (ESI+): t_(R)=17.4-18.2 min, m/z found 354.6, m/z calcd354.3 [M+H]⁺.

(R)-1-(2-(dimethylamino)-3-phenylpropyl)-3-(2-methyl-1-phenylpropan-2-yl)urea

(DD36D)

Yield: 23%. LCMS (ESI+): t_(R)=16.6-17.8 min, m/z found 354.9, m/z calcd354.3 [M+H]⁺

1-((S)-2-(dimethylamino)-3-(3-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DD47LS)

Yield: 59%. LCMS (ESI+): t_(R)=15.0-15.2 min, m/z found 362.7, m/z calcd362.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(3-hydroxyphenyl)propyl)-3-(2-methyl-1-(thiophen-3-yl)propan-2-yl)urea(DD46L)

Yield: 72%. LCMS (ESI+): t_(R)=15.9-16.9 min, m/z found 376.7, m/z calcd376.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-phenylethyl)urea(DD53LS)

Yield: 22%. LCMS (ESI+): t_(R)=10.7-15.0 min, m/z found 342.7, m/z calcd342.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(p-tolyl)ethyl)urea(DD51LS)

Yield: 30%. LCMS (ESI+): t_(R)=9.8-10.0 min, m/z found 356.7, m/z calcd356.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(naphthalen-1-yl)ethyl)urea(DD50LS)

Yield: 31%. LCMS (ESI+): t_(R)=16.3-16.7 min, m/z found 392.8, m/z calcd392.2 [M+H]⁺.

(S)-1-(2,3-dihydro-1H-inden-2-yl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea(DD57L)

Yield: 84%. LCMS (ESI+): t_(R)=9.6-9.9 min, m/z found 354.6, m/z calcd354.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((R)-1-phenylpropan-2-yl)urea(DD61LA)

Yield: 39%. LCMS (ESI+): t_(R)=9.6-9.9 min, m/z found 356.6, m/z calcd356.2 [M+H]⁺. Chiral HPLC: AS-H column, 0.1% diethyl amine inisopropanol/hexane 15:85, 9 mL/min, 25 min: t_(R)=14.2 min.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-phenylpropan-2-yl)urea(DD61LB)

Yield: 39%. LCMS (ESI+): t_(R)=9.6-9.9 min, m/z found 356.6, m/z calcd356.2 [M+H]⁺. Chiral HPLC: AS-H column, 0.1% diethyl amine inisopropanol/hexane 15:85, 9 mL/min, 25 min: t_(R)=21.2 min.

1-((S)-2-(dimethylamino)-3-(6-hydroxypyridin-3-yl)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DD78)

Yield: 20%. LCMS (ESI+): t_(R)=1.0-1.8 min, m/z found 363.0, m/z calcd363.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(2-hydroxypyridin-4-yl)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DD79)

Yield: 20%. LCMS (ESI+): t_(R)=0.8-1.8 min, m/z found 363.0, m/z calcd363.2 [M+H]⁺

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((R)-1-(thiophen-3-yl)butan-2-yl)urea(DD88A)

Yield: 41%. LCMS (ESI+): t_(R)=3.9-4.5 min, m/z found 376.0, m/z calcd376.2 [M+H]⁺. Chiral HPLC: AS-H column, 0.1% diethyl amine inisopropanol/hexane 15:85, 5 mL/min, 28 min: t_(R)=6.6 min.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl)butan-2-yl)urea(DD88B)

Yield: 41%. LCMS (ESI+): t_(R)=4.1-4.6 min, m/z found 376.0, m/z calcd376.2 [M+H]⁺. Chiral HPLC: AS-H column, 0.1% diethyl amine inisopropanol/hexane 15:85, 5 mL/min, 28 min: t_(R)=15.1 min.

1-((S)-3-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(dimethylamino)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DD127)

Yield: 64%. LCMS (ESI+): t_(R)=5.6-6.2 min, m/z found 432.1 m/z calcd432.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)ethyl)urea(DD137)

Yield: 34%. LCMS (ESI+): t_(R)=0.7-1.2 min, m/z found 429.1, m/z calcd429.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(3-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)propyl)urea(DD135)

Yield: 42%. LCMS (ESI+): t_(R)=0.6-1.4 min, m/z found 443.1, m/z calcd443.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(4-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)butyl)urea(DD136)

Yield: 30%. LCMS (ESI+): t_(R)=0.6-1.5 min, m/z found 457.1, m/z calcd457.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((2S)-1-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)propan-2-yl)urea(DD157)

Yield: 65%. LCMS (ESI+): t_(R)=0.5-1.6 min, m/z found 443.1, m/z calcd443.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((2R)-1-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)propan-2-yl)urea(DD175)

Yield: 73%. LCMS (ESI+): t_(R)=0.7-1.4 min, m/z found 443.2, m/z calcd443.2 [M+H]⁺.

1-((S)-3-(4-hydroxyphenyl)-2-(methylamino)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DD196)

Yield: 26%. LCMS (ESI+): t_(R)=2.9-4.0 min, m/z found 348.2, m/z calcd348.2 [M+H]⁺

1-((S)-2-(benzyl(methyl)amino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DD187)

Yield: 92%. LCMS (ESI+): t_(R)=5.3-6.7 min, m/z found 438.2, m/z calcd438.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-fluorophenethyl)urea(DDLM-08)

Yield: 79%. LCMS (ESI+): t_(R)=2.6-5.5 min, m/z found 360.2, m/z calcd360.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(3-fluorophenethyl)urea(DDLM-10)

Yield: 40%. LCMS (ESI+): t_(R)=1.8-3.8 min, m/z found 360.2, m/z calcd360.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(4-fluorophenethyl)urea(DDLM-15)

Yield: 44%. LCMS (ESI+): t_(R)=0.6-4.9 min, m/z found 360.2, m/z calcd360.2 [M+H]⁺.

(S)-1-(3-(4-hydroxyphenyl)-2-(pyrrolidin-1-yl)propyl)-3-phenethylurea(DDLM-14)

Yield: 28%. LCMS (ESI+): t_(R)=2.0-5.3 min, m/z found 368.2, m/z calcd368.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-(pyrazolo[1,5-a]pyridin-3-yl)ethyl)urea(DD208)

Yield: 38%. LCMS (ESI+): t_(R)=0.9-2.8 min, m/z found 382.2, m/z calcd382.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(4-fluoro-2-methoxyphenethyl)urea(DD214)

(9H-fluoren-9-yl)methyl((S)-1-(4-hydroxyphenyl)-3-(3-((S)-1-(thiophen-3-yl)propan-2-yl)ureido)propan-2-yl)carbamate(DD202)

Yield: 34%. LCMS (ESI+): t_(R)=7.6-8.7 min, m/z found 578.2, m/z calcd578.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DDLM19)

Yield: 72%. LCMS (ESI+): t_(R)=5.4-6.9 min, m/z found 418.2, m/z calcd418.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)-3-(1-(thiophen-3-yl)propan-2-yl)urea(BD131L-RS)

A 20 mL microwave vial was charged with [BD130-L] (0.30 g, 1.01 mmol)and triethylamine (0.15 mL, 1.08 mmol) in anhydrous DMF (2 mL) undernitrogen atmosphere. A solution of [(S)-20] (0.11 g, 0.36 mmol) and [20](0.20 g, 0.65 mmol) in DMF (2.5 mL) was added. The mixture was stirredat ambient temperature for 20 h. Then the reaction mixture was dilutedby 25% iPrOH in EtOAc (25 mL) and washed with carbonate buffer (pH 9,3×15 mL). Aqueous washings were back-extracted with EtOAc (15 mL).Combined organic layers were extracted with 0.1 N HCl (3×25 mL).Combined aqueous layers were basified with carbonate buffer to pH 9 andextracted with 25% iPrOH in EtOAc (3×50 mL). Combined organic layerswere dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by dry-column vacuumchromatography (NH₄OH/MeOH/CHCl₃ 0.9:8.1:91).

Diastereomers were separated by preparative HPLC (Chiralpak IC, 0.1%diethylamine in iPrOH/0.1% diethylamine in hexane 30:70, 10 mL/min, 114bar). Yield: 129 mg of BD131LS (48%); 53 mg of BD131LR (42%). TLC(NH₄OH/MeOH/CHCl₃ 1.2:10.8:88) R_(f)=0.47 (KMnO₄ stain).

1-((S)-2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(BD131-LS)

Chiral HPLC: Chiralpak IC column, 0.1% diethylamine in iPrOH/0.1%diethylamine in hexane 30:70, 10 mL/min, 114 bar, 6 min: t_(R)=3.0 min.LCMS (STANDESI): t_(R)=2.9 min, purity: 98% (254 nm); m/z found 390.7,calcd. 390.6 for C₁₃H₂₃N₂O [M-Cl]⁺.1H NMR (360 MHz, CDCl₃) δ ppm 7.23(dd, J=4.9, 3.0 Hz, 1H), 6.95-6.99 (m, 1H), 6.93 (dd, J=4.9, 1.2 Hz,1H), 6.49 (s, 2H), 5.03 (br. d, J=6.2 Hz, 1H), 4.39 (br. d, J=7.7 Hz,1H), 3.94 (spt, J=6.6 Hz, 1H), 3.09 (ddd, J=12.8, 6.8, 4.2 Hz, 1H), 2.97(ddd, J=12.4, 10.0, 1.7 Hz, 1H), 2.80 (dd, J=14.0, 5.2 Hz, 1H),2.69-2.84 (m, 2H), 2.71 (dd, J=14.0, 6.9 Hz, 1H), 2.50 (dd, J=13.1, 10.9Hz, 1H), 2.37 (s, 6H), 2.25 (s, 6H), 1.07 (d, J=6.6 Hz, 3H). ¹³C NMR (91MHz, CDCl₃) d ppm 157.9, 154.4, 138.5, 137.7 (2C), 129.0, 126.4, 125.3,122.0, 115.6 (2C), 63.3, 46.6, 40.3, 39.8 (2C), 37.5, 23.2, 20.7, 20.6(2C). HR-ESIMS: m/z found 390.2219; calcd. 390.2210 for C₂₁H₃₂N₃O₂S([M+H]⁺). [α]_(D) ²⁴=+22.9° (c 0.59, CHCl₃).

1-((S)-2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)-3-((R)-1-(thiophen-3-yl)propan-2-yl)urea(BD131-LR)

Chiral HPLC: Chiralpak IC column, 0.1% diethylamine in iPrOH/0.1%diethylamine in hexane 30:70, 10 mL/min, 114 bar, 6 min: t_(R)=4.5 min.LCMS (STANDESI): t_(R)=2.9 min, purity: 98% (254 nm); m/z found 390.7,calcd. 390.6 for C₁₃H₂₃N₂O [M-Cl]⁺. 1H NMR (360 MHz, CDCl₃) δ ppm 7.22(dd, J=4.9, 3.0 Hz, 1H), 6.94-6.98 (m, 1H), 6.92 (dd, J=4.9, 1.3 Hz,1H), 6.49 (s, 2H), 5.04 (br. d, J=5.5 Hz, 1H), 4.49 (br. d, J=6.2 Hz,1H), 3.94 (spt, J=6.8 Hz, 1H), 3.09 (ddd, J=12.5, 6.9, 4.4 Hz, 1H), 2.98(ddd, J=12.4, 10.0, 1.7 Hz, 1H), 2.80 (dd, J=14.0, 4.5 Hz, 1H),2.71-2.79 (m, 2H), 2.71 (dd, J=14.0, 7.0 Hz, 1H), 2.50 (dd, J=13.2, 11.0Hz, 1H), 2.38 (s, 6H), 2.24 (s, 6H), 1.06 (d, J=6.6 Hz, 3H). ¹³C NMR (91MHz, CDCl₃) d ppm 157.9, 154.4, 138.6, 137.7 (2C), 129.0, 126.3, 125.3,121.9, 115.6 (2C), 63.6, 46.6, 40.1, 39.8 (2C), 37.5, 23.2, 20.6, 20.6(2C). HR-ESIMS: m/z found 390.2219; calcd. 390.2210 for C₂₁H₃₂N₃O₂S([M+H]⁺). [α]_(D) ²⁴=+32.8° (c 0.48, CHCl₃).

1-((S)-2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)-3-(2-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)ethyl)urea(DD140)

DD140 was synthesized according the procedure for BD131L-RS usingBD130-L and DD126 as starting materials. Yield: 59%. LCMS (ESI+):t_(R)=0.6-1.4 min, m/z found 457.1, m/z calcd 457.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)-3-(2-(thiophen-3-yl)ethyl)urea(DD34L)

DD34L was synthesized according the procedure for BD131L-RS usingBD130-L and DD14 as starting materials. Yield: 48%. LCMS (ESI+):t_(R)=9.3-10.4 min, m/z found 376.7, m/z calcd 376.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-1-isopropyl-3-((S)-1-(naphthalen-1-yl)ethyl)urea(DD50NP)

DD50NP was synthesized according Method A using DD27NP((S)-4-(2-(dimethylamino)-3-(isopropylamino)propyl)phenol) and DD49-S asstarting materials. Yield: 17%. LCMS (ESI+): t_(R)=10.5-10.7 min, m/zfound 434.9, m/z calcd 434.3 [M+H]⁺.

Method B: Alternative Method for Synthesis of Urea Compounds

DD180 was weighed in a microwave tube and solved in dry DMF. R—NH₂ wasadded, the tube sealed and the reaction mixture stirred at 70° C.overnight under inert atmosphere. H₂O demin. was added and the mixturelyophilisated. The crude product was purified by preparative HPLC givingthe corresponding formates or trifluoroacetates.

Compounds Synthesized Following Method B(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-methoxyphenethyl)urea(DD198)

Yield: 21%. LCMS (ESI+): t_(R)=3.0-4.4 min, m/z found 372.1, m/z calcd372.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(3-methoxyphenethyl)urea(DD200)

Yield: 20%. LCMS (ESI+): t_(R)=3.5-4.6 min, m/z found 372.2, m/z calcd372.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(4-methoxyphenethyl)urea(DD201)

Yield: 27%. LCMS (ESI+): t_(R)=2.7-4.1 min, m/z found 372.2, m/z calcd372.2 [M+H]⁺.

(S)-1-(2-(benzo[b]thiophen-3-yl)ethyl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea(DD203)

Yield: 25%. LCMS (ESI+): t_(R)=5.1-5.7 min, m/z found 398.1, m/z calcd398.2 [M+H]⁺.

1-allyl-1-((S)-2-(dimethylamino)-3-phenylpropyl)-3-(1-(thiophen-3-yl)propan-2-yl)urea(DD93AB)

(S, R/S)-12 (1 eq) and Sodium Hydride (60% suspension in oil, 21.5 eq)were weighed in a microwave tube and suspended in dry THF. The mixturewas stirred in an ice-water-bath and 1,3-Dibromopropan (5 eq) was slowlyadded. The reaction vessel was allowed to warm up to room temperatureand stirred overnight. Then the mixture was stirred at refluxtemperature for 8 h. The reaction mixture was quenched by addition ofice. The suspension was diluted with CHCl₃, washed with sat. NaHCO₃solution and extracted with 0.1N HCl. Combined aqueous extracts werebasified with 0.1N NaOH to pH>10 and back-extracted with ethyl acetate.Combined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. Purification and separation ofdiastereomeres was performed using flash chromatography. Yield: 54%.LCMS (ESI+): t_(R)=5.7-6.0 min or 6.0-6.2 min, m/z found 386.1, m/zcalcd 386.2 [M+H]⁺.

(S)—N-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-4-phenylbutanamide(DD91)

4-Phenylbutanoic acid (1 eq) in a Schlenk flask was solved in dry DMFand stirred under N₂ atmosphere in an ice-water-bath. DIPEA (1.2 eq),HATU (1.1 eq) and then 35 (1.1 eq) were added. The mixture was allowedto warm up to room temperature and was stirred for 15 h. Water was addedand the aqueous mixture was extracted with EtOAc. The organic layer waswashed with sat. NaHCO₃ solution and H₂O dem. The organic layer wasdried (Na₂SO₄), filtered and concentrated under reduced pressure. Theresidue was purified by preparative HPLC. Yield: 17%. LCMS (ESI+):t_(R)=4.8-5.2 min, m/z found 341.2, m/z calcd 341.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-(thiophen-3-yl)ethyl)thiourea(DD81)

3-(2-isothiocyanatoethyl)thiophene (4.5 eq) in a microwave tube solvedin dichloromethane was stirred in an ice-water-bath. 35 (1 eq) and TEA(2.2 eq) solved in dry DMF were added slowly. The mixture was allowed towarm up to room temperature and stirred for 7 h. The solvent was thenevaporated, the residue diluted with isopropanol/EtOAc (1:3) and washedwith a saturated aqueous solution of NaHCO₃. The organic layer wasextracted with 0.1N HCl-solution and the aqueous extracts were adjustedto pH 9 with saturated aqueous NaHCO₃/Na₂CO₃ solution and finallyextracted with EtOAc. The organic layers were dried (Na₂SO₄), filteredand concentrated under reduced pressure. The residue was purified bypreparative HPLC. Yield: 20%. LCMS (ESI+): t_(R)=9.3-9.8 min, m/z found364.5, m/z calcd 364.2 [M+H]⁺.

2-(thiophen-3-yl)ethyl(S)-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)carbamate (DD77)

DD77 was synthesized according Method A using 4-nitrophenyl(2-(thiophen-3-yl)ethyl) carbonate (1 eq) and compound 35 as startingmaterials. Yield: 58%. LCMS (ESI+): t_(R)=8.7-9.5 min, m/z found 349.5,m/z calcd 349.2 [M+H]⁺.

(S)-1-(2-((2-chloroethyl)(methyl)amino)-3-(4-hydroxyphenyl)propyl)-3-phenethylurea(DD185)

Compound 39 was solved in dichloroethane. An high excess of sodiumtriacetoxyborohydride was added and subsequently a high excess ofchloroacetaldehyde (50 wt. %). After 10 minutes of vigorous stirring,the reaction was cooled in an ice-water-bath and quenched with sat.NaHCO₃ solution and extracted with dichloromethane. Combined organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by preparative HPLC givingthe corresponding trifluoroacetate. Yield: 54%. LCMS (ESI+):t_(R)=3.5-4.9 min, m/z found 390.2, m/z calcd 390.2 [M+H]⁺.

(S)-1-(2-((2-hydroxyethyl)(methyl)amino)-3-(4-hydroxyphenyl)propyl)-3-phenethylurea(DD186)

DD182 was dissolved in EtOH in a Schlenk flask and stirred under N₂atmosphere. 10% Pd—C were added and the mixture was stirred for 5 hunder H₂ atmosphere at ambient temperature. The suspension was filteredthrough celite, the filtrate was evaporated and the residue was purifiedby preparative HPLC giving the corresponding formate. Yield: 60%. LCMS(ESI+): t_(R)=1.3-3.1 min, m/z found 372.2, m/z calcd 372.2 [M+H]⁺

1-((S)-2-(dimethylamino)-3-(4-hydroxy-3-(hydroxymethyl)phenyl)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DD131)

DD127 was solved in a mixture of MeOH/TFA (1:1) and stirred under inertatmosphere at room temperature for 16 h. The solvent was evaporated, theresidue diluted with water, lyophilisated and purified by preparativeHPLC giving the corresponding trifluoroacetate. Yield: 48%. LCMS (ESI+):t_(R)=2.7-3.5 min, m/z found 392.1, m/z calcd 392.2 [M+H]⁺.

Method C: CuAAc-Reaction

(S)-1-(But-3-yn-1-yl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea(46) (1 eq), CuSO₄×5H₂O (0.2 eq), sodium ascorbate (0.5 eq) and R—N₃(2-5 eq) were dissolved in a mixture of DMF/H₂O (2:1 (v/v)) and stirredat room temperature for 6 h. The reaction mixture was quenched with 0.1MEDTA-solution, adjusted to pH 2-3 with 0.1 N HCl and washed with DCM(3×). Then the aqueous phase was adjusted to pH 8-9 with saturatedaqueous NaHCO₃/Na₂CO₃ solution and extracted with EtOAc. Combinedorganic layers were dried (Na₂SO₄), filtered and concentrated underreduced pressure. The residue was purified by preparative HPLC.

Compounds Synthesized Following Method C(S)-1-(2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethyl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea(DD154)

Yield: 78%. LCMS (ESI+): t_(R)=2.2-4.1 min, m/z found 423.2, m/z calcd423.2 [M+H]⁺.

(S)-1-(2-(1-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)ethyl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea(DD161)

Yield: 21%. LCMS (ESI+): t_(R)=0.6-1.8 min, m/z found 490.2, m/z calcd490.3 [M+H]⁺.

(S)-1-(2-(1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)ethyl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea(DD165)

Yield: 21%. LCMS (ESI+): t_(R)=0.6-2.1 min, m/z found 534.2, m/z calcd534.3 [M+H]⁺.

S)-1-(2-(1-(17-azido-3,6,9,12,15-pentaoxaheptadecyl)-1H-1,2,3-triazol-4-yl)ethyl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea(DD168)

Yield: 23%. LCMS (ESI+): t_(R)=0.7-4.0 min, m/z found 622.3, m/z calcd622.4 [M+H]⁺.

N-(17-(4-(2-(3-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)ureido)ethyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)-5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamide(DD170)

Yield: 52%. LCMS (ESI+): t_(R)=4.4-4.8 min, m/z found 822.5, m/z calcd822.5 [M+H]⁺.

Method D: Retro-Diels-Alder

Compounds DD135, DD136, DD137, DD140, DD157 and DD175 were weighed in amicrowave tube and suspended in toluene. The tube was sealed and themixture stirred at reflux temperature for 8 h. The solvent wasevaporated and the product was obtained after purification bypreparative HPLC giving the corresponding trifluoroacetates.

Compounds Synthesized Following Method D(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)urea(DD120)

Yield: 20%. LCMS (ESI+): t_(R)=0.7-1.2 min, m/z found 361.1, m/z calcd361.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propyl)urea(DD138)

Yield: 20%. LCMS (ESI+): t_(R)=0.6-1.6 min, m/z found 375.1, m/z calcd375.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-(4-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl)urea(DD139)

Yield: 45%. LCMS (ESI+): t_(R)=1.0-1.5 min, m/z found 389.1, m/z calcd389.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propan-2-yl)urea(DD158)

Yield: 51%. LCMS (ESI+): t_(R)=0.7-1.5 min, m/z found 375.1, m/z calcd375.2 [M+H]⁺.

1-((S)-2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-3-((R)-1-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propan-2-yl)urea(DD179)

Yield: 56%. LCMS (ESI+): t_(R)=0.8-1.6 min, m/z found 375.1, m/z calcd375.2 [M+H]⁺.

(S)-1-(2-(dimethylamino)-3-(4-hydroxy-2,6-dimethylphenyl)propyl)-3-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)urea(DD144)

Yield: 67%. LCMS (ESI+): t_(R)=0.8-1.5 min, m/z found 389.1, m/z calcd389.2 [M+H]⁺.

1-((S)-3-(3,4-dihydroxyphenyl)-2-(dimethylamino)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DDLM20)

DDLM19 was stirred in 1M HCl solution for 4 h at 65° C. The mixture wasdiluted with water, lyophilisated and purified by preparative HPLCgiving the corresponding trifluoroacetate. Yield: 75%. LCMS (ESI+):t_(R)=2.3-3.3 min, m/z found 378.1, m/z calcd 378.2 [M+H]⁺.

1-((S)-2-amino-3-(4-hydroxyphenyl)propyl)-3-((S)-1-(thiophen-3-yl)propan-2-yl)urea(DD206)

DD202 was stirred in 25% piperidine in DMF for 0.5 h. The mixture wasdiluted with MeOH and the solvent evaporated. Purification bypreparative HPLC gave the corresponding formate as a white powder.Yield: 60%. LCMS (ESI+): t_(R)=2.1-4.6 min, m/z found 334.1, m/z calcd334.2 [M+H]⁺.

Method E: General Method for N-Debenzylation

Benzylated compound (1 eq) was dissolved in MeOH in a Schlenk flask andstirred under N₂ atmosphere. 1,1,2-Trichloroethane (2 eq) and 10% Pd—Cwere added and the mixture was stirred for 2-5 h under H₂ atmosphere atambient temperature. The suspension was filtered through celite, thefiltrate was evaporated and the residue was purified by flashchromatography or preparative HPLC.

Compounds Synthesized Following Method E(S)-1-(2-(1H-1,2,3-triazol-4-yl)ethyl)-3-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)urea(DD156)

Yield: 57%. LCMS (ESI+): t_(R)=0.8-1.2 min, m/z found 333.1, m/z calcd333.2 [M+H]⁺.

(S)-4-(3-amino-2-(methylamino)propyl)phenol (DD195)

(S)-1-(2-((2-(benzyloxy)ethyl)(methyl)amino)-3-(4-hydroxyphenyl)propyl)-3-phenethylurea(DD182)

Compound 39 (1 eq) was weighed in a microwave tube and solved in dryDMF. NaHCO₃ (6.1 eq) and 2-(benzyloxy)ethyl methanesulfonate (6.5 eq)were added, the tube sealed and the mixture stirred at 100° C. for 15 hunder inert atmosphere. The mixture was the diluted with EtOAc andwashed with sat. NaHCO₃ solution. The organic layer was dried (Na₂SO₄),filtered and concentrated under reduced pressure. The residue waspurified by flash chromatography. Yield: 50%. LCMS (ESI+): t_(R)=5.8-6.7min, m/z found 462.3, m/z calcd 462.3 [M+H]⁺.

Method F: General Method for Synthesis of 4-Nitrophenyl-R¹-Carbamates

4-Nitrophenyl chloroformate (2 eq) in a Schlenk flask was solved in dryTHF and stirred under N₂ atmosphere in an ice-water-bath. A mixture ofR¹—NH₂ (1 eq) and triethylamine (1-2 eq) in dry THF was added dropwise.The reaction mixture was allowed to warm up to room temperature and wasstirred for 3-8 h. The mixture was diluted with dichloromethane,filtered and the filtrate was washed with saturated aqueous NaHCO₃ andbrine. The organic layer was dried (Na₂SO₄), filtered and concentratedunder reduced pressure. The residue was purified by flash chromatography(100% dichloromethane) to give the product as a white solid aftertrituration with hexane.

Compounds Synthesized Following Method F 4-Nitrophenyl(2-(thiophen-3-yl)ethyl)carbamate (DD14)

4-nitrophenyl (2-methyl-1-(thiophen-3-yl)propan-2-yl)carbamate (DD24)

4-nitrophenyl (S)-(1-phenylethyl)carbamate (DD52)

4-nitrophenyl (S)-(1-(naphthalen-1-yl)ethyl)carbamate (DD49)

4-nitrophenyl (S)-(1-(p-tolyl)ethyl)carbamate (DD48)

4-nitrophenyl (2,3-dihydro-1H-inden-2-yl)carbamate (DD56)

4-nitrophenyl (2-(pyrazolo[1,5-a]pyridin-3-yl)ethyl)carbamate (AU-10)

4-nitrophenyl (1-(thiophen-3-yl)butan-2-yl)carbamate (DD87)

4-nitrophenyl((2S)-1-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)propan-2-yl)carbamate(DD153)

4-nitrophenyl(4-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)butyl)carbamate(DD134)

4-nitrophenyl(2-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)ethyl)carbamate(DD126)

4-nitrophenyl(3-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)propyl)carbamate(DD133)

4-nitrophenyl((2R)-1-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)propan-2-yl)carbamate(DD173)

(S)—N-(2-(dimethylamino)-3-(4-hydroxyphenyl)propyl)-1H-imidazole-1-carboxamide(DD180)

Compound 35 (1 eq) in a Schlenk flask was solved in dry DMF and stirredunder N₂ atmosphere in an ice-water-bath. A mixture of CDI (1 eq) in dryDMF was added dropwise. The reaction mixture was allowed to warm up toroom temperature and was stirred overnight. H₂O demin. was added and themixture lyophilisated. The product was used in the following stepswithout further purification.

Method G: Reduction of Amides

1M Borane-tetrahydrofurane complex (6.1 eq) was slowly added tosuspension of Amide (1 eq) in anhydrous THF under cooling with ice bath.The mixture was refluxed for 15 h (except for DD199 stirring at roomtemperature) under nitrogen atmosphere and then quenched with anhydrousmethanol on ice. The mixture was refluxed again for 1 h. The solvent wasthen removed under reduced pressure and dilution-evaporation sequencewas repeated with anhydrous methanol. The residue was resuspended inmethanol with addition of 37% aqueous HCl (except for DD122 and DDLM18)and concentrated under reduced pressure, diluted with ethanol andevaporated again (repeated twice). Purification either by HCl saltformation and/or flash chromatography.

Compounds Synthesized Following Method G(S)-4-(3-amino-2-(dimethylamino)propyl)pyridin-2-ol (DD74)

(S)-5-(3-amino-2-(dimethylamino)propyl)pyridin-2-ol (DD76)

(S)-3-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-N²,N²-dimethylpropane-1,2-diamine(DD122)

(S)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-N²,N²-dimethylpropane-1,2-diamine(DDLM18)

(S)-4-(3-amino-2-(pyrrolidin-1-yl)propyl)phenol (DDLM12)

(S)-3-(3-amino-2-(dimethylamino)propyl)phenol (DD45)

(9H-fluoren-9-yl)methyl(S)-(1-amino-3-(4-hydroxyphenyl)propan-2-yl)carbamate (DD199)

Method H: Reductive Methylation of Primary Amines

To a suspension of amino amides (1 eq) in acetonitrile/water (9:1 v/v),37% aqueous formaldehyde (10 eq) was added followed by sodiumtriacetoxyborohydride (5 eq). The mixture was stirred for 10 min at anambient temperature and then quenched by saturated NaHCO₃. The pH wasadjusted to 8-9 by addition of sat. NaHCO₃/Na₂CO₃ solution, and themixture was extracted with isopropanol/ethyl acetate (1:3 v/v). Combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography.

Compounds Synthesized Following Method H(S)-3-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(dimethylamino)propanamide(DD117)

(S)-2-(dimethylamino)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanamide(DDLM17)

(S)-2-(dimethylamino)-3-(2-hydroxypyridin-4-yl)propanamide (DD71)

(S)-2-(dimethylamino)-3-(6-hydroxypyridin-3-yl)propanamide (DD72)

(S)-2-(dimethylamino)-3-(3-hydroxyphenyl)propanamide (DD42)

Method I: Aminolysis of carboxylic acid esters

Carboxylic acid esters (1 eq) were solved in dry methanol and stirred at−10° C. in an acetone-ice-bath. Dry ammonia gas was bubbled through thesolution for 30 minutes at −10° C. and the solution was then allowed towarm up to room temperature and stirred overnight. After full conversionof starting material the solvent was evaporated and dried under highvacuum overnight. No further purification was required.

Compounds Synthesized Following Method I(S)-2-amino-3-(2-hydroxypyridin-4-yl)propanamide (DD68)

(S)-2-amino-3-(6-hydroxypyridin-3-yl)propanamide (DD69)

Method J: Amidation of Carboxlic Acids

Carboxylic acids (acetonide- and fmoc-protected, 1 eq) was solved inacetonitrile. EEDQ (1.1 eq) and subsequently NH₄HCO₃ (3 eq) were added.The mixture was stirred at room temperature for 20 h. Then theprecipitate was filtered off, washed with H₂O dem. and chloroform.Combined filtrates were washed with 5% NaHCO₃ solution and the combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography.

Compounds Synthesized Following Method J (9H-fluoren-9-yl)methyl(S)-(1-amino-3-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-1-oxopropan-2-yl)carbamate(DD112)

(9H-fluoren-9-yl)methyl(S)-(1-amino-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)carbamate(DDLM11)

(S)-2-amino-3-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)propanamide(DD116)

DD112 (1 eq) was solved in dichloromethane, DBU (2.5 eq) was added andthe mixture was stirred for 2.5 h at room temperature. The solvent wasevaporated and the residue purified by flash chromatography. Yield: 76%.

(S)-2-amino-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanamide (DDLM16)

DDLM11 (1 eq) was stirred in 25% piperidine in DMF for 75 min. Themixture was diluted with MeOH and the solvent evaporated. The residuewas purified by flash chromatography. Yield: 70%

2-((R)-2-aminopropyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione(DD 172

tert-butyl (R)-(1-aminopropan-2-yl)carbamate hydrochloride (1 eq) in amicrowave tube was solved in MeOH. Na₂CO₃ (2 eq) and TBAB (0.26 eq) wasadded and the mixture was stirred in an ice-water-bath.3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1,3-dione (1 eq) in a flask,suspended in MeOH was also stirred in an ice-water-bath for 10 minutesand then slowly added to the reaction mixture. The mixture was allowedto warm up to room temperature and stirred for 1 h. DMS (1.5 eq) wasadded, the tube sealed and the mixture was stirred at 70° C. overnight.Then the mixture was allowed to cool to room temperature, chloroform and0.1 N NaOH was added, the layers separated and the aqueous phase washedwith chloroform. Combined organic layers were washed with 0.1 N NaOH,0.1 N HCl and brine and the dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was solved indichloromethane/TFA (10:1) at 0° C. The mixture was allowed to warm upto room temperature and then stirred for 3 h. It was diluted with MeOHand the solvent evaporated. The residue was solved in sat. NaHCO₃solution, the pH adjusted with NH_(3conc) to 10 and extracted withchloroform (10×). Combined organic layers were dried over anhydrousNa₂SO₄, filtered, and concentrated under reduced pressure. Yield: 52%

2-((S)-2-aminopropyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione(DD151)

DD151 was synthesized as described for DD172, using tert-butyl(S)-(1-aminopropan-2-yl)carbamate (1 eq) and3a,4,7,7a-tetrahydro-4,7-epoxyisobenzofuran-1,3-dione (1 eq) as startingmaterials. Yield: 10%.

(S)-3-(4-hydroxyphenyl)-2-(pyrrolidin-1-yl)propanamide (DDLM5)

L-Tyrosinamide (1 eq) was solved in dry DMF in a microwave tube.1,4-dibromobutane was added, the tube sealed and the mixture stirred for5 h at room temperature and for 15 h at 50° C. under inert atmosphere.DDLM5×HBr precipitated and could be filtered off and subsequentlypurified by flash chromatography. Yield: 35%

A mixture of Boc-L-Dmt-OH (0.62 g, 2.0 mmol), pyridine (0.16 mL, 2.0mmol), di-tert-butyl dicarbonate (1.0 mL, 4.3 mmol), and ammoniumbicarbonate (0.32 g, 4.1 mmol) in anhydrous dioxane (5 mL) was sealed ina microwave tube and stirred vigorously for 4 h at ambient temperature.Then the mixture was filtered and the precipitate was washed with ethylacetate (2×2 mL). The filtrate was concentrated under reduced pressureand the obtained residue was redissolved in EtOAc (20 mL) and washedwith 0.1 N HCl (2×15 mL), saturated aqueous NaHCO₃ (2×10 mL) andsaturated aqueous NaCl (10 mL). Organic layer was dried over anhydrousNa₂SO₄, filtered and the solvent was removed under reduced pressure.White solid residue was dissolved in 2N HCl in diethyl ether (10.0 mL,20.0 mmol), sonicated, and stirred for 20 h at ambient temperature.After 20 h the product precipitated. The slurry was filtered and theprecipitate was washed with diethyl ether (2×10 mL). The white solid wasdried under high vacuum yielding 0.474 g (97%) of the desired product.It was used in the next step without further purification.

TLC (NH₄OH/MeOH/CHCl₃ 2:18:80): R_(f) (prod)=0.46 (ninhydrin stain).LCMS: t_(R)=9.9 min, purity: 96%; m/z found: 231.4; calcd. 231.3([M+Na]⁺). ¹H NMR (600 MHz, DMSO-d₆) d ppm 9.10 (br. s., 1H), 8.42 (br.s., 3H), 7.36 (s, 1H), 7.35 (s, 1H), 6.41 (s, 2H), 3.65 (dquin, J=11.0,5.3 Hz, 1H), 2.98 (dd, J=13.8, 11.0 Hz, 1H), 2.90 (ddd, J=13.8, 5.3, 3.0Hz, 1 H), 2.19 (s, 6H). ¹H NMR (600 MHz, DMSO-d₆, exchange with D₂O) dppm 7.40 (s, 1H), 7.34 (s, 1H), 6.42 (s, 2H), 3.66 (dd, J=10.8, 4.7 Hz,1H), 2.99 (dd, J=13.8, 10.8 Hz, 1H), 2.87 (dd, J=13.8, 4.7 Hz, 1H), 2.19(s, 6H)¹³C NMR (151 MHz, DMSO-d₆) δ ppm 170.2, 155.6, 138.4 (2C), 122.2,114.9 (2C), 51.6, 30.5, 20.0 (2C). [α]_(D) ²⁵=+83.9° (c 0.38, H₂O).

BD128L (474 mg, 1.94 mmol) was suspended in a mixture of MeCN (15 mL)and water (2.5 mL). To the mixture 37% aqueous formaldehyde (1.5 mL, 20mmol) was added, followed by sodium triacetoxyborohydride (1.65 g, 7.8mmol). The mixture was stirred at ambient temperature for 15 min. Thereaction was quenched with saturated aqueous NaHCO₃ (15 mL, gasrelease). The layers were separated. pH of aqueous layer was adjusted to8 by addition of solid Na₂CO₃, it was filtered and extracted by 20%iPrOH in EA (3×15 mL). Combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure yielding whitesolid (450 mg, 98%) after drying under high vacuum. The product wasobtained and characterized as free base since it was easier to handle inthis form.

TLC (NH₄OH/MeOH/CHCl₃ 1.5:13.5:85): R_(f) (prod)=0.49 (KMnO₄ stain).LCMS (STANDESI): t_(R)=2.9 min, purity: 99% (254 nm); m/z found 237.5,calcd. 237.3 for C₁₃H₂₁N₂O₂ [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ ppm 8.91(br. s., 1H), 7.06 (br. s., 1H), 6.74 (br. s., 1H), 6.35 (s, 2H), 3.00(dd, J=9.3, 3.6 Hz, 1H), 2.94 (dd, J=13.4, 9.3 Hz, 1H), 2.56 (dd,J=13.4, 3.6 Hz, 1H), 2.27 (s, 6H), 2.19 (s, 6H). ¹H NMR (600 MHz,DMSO-d₆, exchange with D₂O) d ppm 6.36 (s, 2H), 3.01 (dd, J=9.4, 3.8 Hz,1H), 2.95 (dd, J=13.4, 9.3 Hz, 1H), 2.57 (dd, J=13.4, 3.8 Hz, 1H), 2.27(s, 6H), 2.19 (s, 6H). ¹³C NMR (151 MHz, DMSO-d₆) d ppm 172.3, 154.7,137.6 (2C), 126.5, 114.7 (2C), 67.1, 41.8 (2C), 28.9, 20.1 (2C).HRESI-MS: m/z found: 237.1597, calcd. 237.1598 for C₁₃H_(2i)N₂O₂([M+H]⁺). [α]_(D) ²⁵=+57.9° (c 0.51, MeOH).

In a screw-cap tube to a suspension of crude BD129L (0.43 g, 1.84 mmol)in anhydrous THF (3 mL) borane tetrahydrofurane complex (13 mL, 13 mmol)was added at ambient temperature. The reaction tube was sealed and themixture was vigourously stirred at 65-70° C. for 20 h. Then the reactionwas quenched with MeOH, concentrated under reduced pressure, anddilution-concentration sequence was repeated twice more and theresulting yellow residue was dried under high vacuum. Then the crudeproduct was diluted with EtOH (25 mL), 36% aqueous HCl was added (3 mL)and the mixture was concentrated under reduced pressure,dilution-concentration sequence was repeated twice more with EtOH. Theresulting white solid was dissolved in hot EtOH (15 mL), filtered andthe filtrate was concentrated under reduced pressure. The residue wassuspended in acetone (15 mL), filtered, the solids were washed withadditional acetone (15 mL) and dried under high vacuum. Yield: 0.40 g(98%).

TLC (NH₄OH/MeOH/CHCl₃ 3:27:70) R_(f)=0.50 (KMnO₄ and nynhydrin stain).LCMS (STANDESI): t_(R)=2.9 min, purity: 99% (254 nm); m/z found 223.5,calcd. 223.3 for C₁₃H₂₃N₂O [M−H-2Cl]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ ppm11.10 (br. s., 1H), 9.27 (br. s., 1H), 8.45 (s, 3H), 6.49 (s, 2H), 3.89(br. s., 1H), 3.55 (br. s., 1H), 3.12 (d, J=13.2 Hz, 1H), 2.78-3.08 (m,6H), 2.69 (t, J=13.1 Hz, 1H), 2.57 (d, J=14.0 Hz, 1H), 2.23 (s, 6H).HRESI-MS: m/z found: 223.1802; calcd. 223.1805 for C₁₃H₂₃N₂O([M-Cl—H]⁺). [α]_(D) ²⁶=−4.3° (c 0.52, H₂O).

PZM Analogs

binding affinity K_(i) [nM]—number of independent experiments (n) MM1(MOR Compound N127C) hMOR hKOR hDOR Morphine  

(5) 32 (15) 52 (10) 1200 (10) 1800 Naloxone  

(8) 3.7 (21) 4.1 (26) 23 (20) 57 DAMGO  

(5) 25 (5) 3300 (5) 980 TRV 130  

(3) 27 DD 17  

(2) 4200 (2) 8100 (2) 25000 DD 18  

(2) 350 (2) 3100 (2) 4500 BD 127DR  

(2) 2900 (2) 5000 (2) 12000 BD 127DS  

(2) 2400 (2) 3100 (2) 11000 BD 127LR  

(3) 380 (3) 1300 (3) 1800 BD 127LS  

(2) 140 (2) 1000 (2) 2800 DD 93A  

(3) 3200 (2) 1700 (3) ~15000 DD 93B  

(4) 4100 (3) 3100 (4) ~15000 DD 35D  

(2) 180 (2) 960 (2) 2400 DD 35L  

(2) 210 (2) 790 (2) 3000 DD 36D  

(2) 640 (2) 1100 (2) 1000 DD 36L  

(2) 490 (3) 930 (3) 3300 DD 15  

(2) 1500 (2) 5200 (2) 11000 DD 16  

(6) 43 (3) 150 (3) 330 DD 81  

(6) 29 (4) 86 (4) 70 DD 77  

(5) 170 (3) 190 (3) 570 DD 108  

(7) 610 (2) 340 (2) 1700 DD 102  

(5) 320 (2) 160 (2) 1200 DD 109  

(7) 490 (2) 220 (2) 4200 DD 181  

(3) 290 DD 184  

(3) 760 BD 122DR  

(2) 290 (2) 3100 (2) 4100 BD 122DS  

(2) 480 (2) 2300 (2) 4800 BD 122LR  

(4) 42 (4) 190 (4) 88 DD 88A R configuration according to R_(T)  

(4) 96 (2) 60 (2) 470 BD 122LS (PZM21)  

(3) 46 (8) 37 (2) 18 (2) 1000 DD 88B S configuration according to R_(T) 

(4) 41 (4) 4.5 (4) 570 DD 90  

(5) 47 (2) 45 (2) 250 DD 91  

(7) 72 (2) 100 (3) 370 DD 61L-A R configuration according to R_(T)  

(2) 81 (2) 67 (2) 91 DD 61L-B S configuration according to R_(T)  

(2) 42 (2) 37 (2) 360 DD 63L-RS Diastereomers Equal mixture of  

  and  

(2) 14 (2) 19 (2) 44 DD 63L-LA R configuration according to R_(T)  

(3) 43 (3) 67 (3) 83 DD 63L-LB S configuration according to R_(T)  

(3) 8.3 (3) 22 (3) 110 DD 53 LS  

(3) 38 (3) 35 (3) 590 DD 51 LS  

(3) 150 (3) 180 (3) 700 DD 50 LS  

(4) 85 (4) 74 (4) 540 DD 50 NP  

(1) 400 (1) 920 (1) 570 DD 57L  

(3) 7.7 (3) 51 (3) 56 DD 32D  

(3) 310 (3) 1300 (3) 2900 DD 32L  

(4) 38 (4) 46 (4) 650 DD 33D  

(3) 460 (3) 1500 (3) 3600 DD 33L  

(3) 46 (3) 91 (3) 920 DD 47LS  

(3) 34 (4) 46 (4) 350 DD 46L  

(3) 25 (3) 32 (3) 190 DD 79 I  

(3) 210 (3) 1200 (3) 4100 DD 78  

3800 (1) 4600 (2) 12000 (3) >20000 DD 131  

(2) 66 (2) 86 (2) 1500 DD 34L (ANTAGONIST)  

(3) 6.2 (3) 27 (3) 51 BD 131LR  

(4) 4.1 (4) 12 (4) 17 BD 131LS  

(3) 12 (3) 6.5 (3) 85 DD 120 D1 (covalent compound)  

(4) 3.7 (9) 240 (3) 600 (3) 450 DD 138  

(2) 4.7 (3) 580 (3) 450 (3) 3100 DD 139  

(5) 5.9 (3) 1000 (2) 760 (3) 4900 DD 144 (ANTAGONIST, Covalent)  

(3) 0.93 (3) 18 (2) 200 (2) 150 DD 158  

(3) 5.6 (4) 410 (2) 1200 (2) 860 DD 179  

(4) 0.13 + 290 (4) 90 (2) 690 (2) 210 DD 159  

(4) 34 (4) 420 (2) 1500 (2) 3900 DD 156  

(2) 630 (2) 960 (2) 1400 (2) 4700 DD 154  

(3) 200 (2) 1400 (3) 580 DD 161 (n = 2)  

(4) 4700 (3) 1200 (2) 3000 DD 165 (n = 3)  

(5) 3500 (2) 2900 (3) 3900 DD 168 (n = 5)  

(2) 13000 DD 170 (biotin tag)  

(2) 13000 DD185  

(4) 47 (4) 47 (2) 250 (2) 360 DD186  

(2) 970 (2) 1300 (2) 1800 DD196  

(2) 81 (2) 240 (3) 700 DD187  

(2) 220 (2) 210 (2) 720 DD198  

(3) 22 (3) 140 (3) 150 DD200  

(2) 110 (2) 1300 (2) 220 DD201  

(2) 330 (2) 1500 (2) 10000 DDLM-08  

(3) 43 (3) 440 (2) 53 DDLM-10  

(3) 36 (3) 170 (2) 250 DDLM-15  

(3) 27 (3) 190 (1) 250 DDLM-14  

(3) 660 (3) 770 (3) 1500 DD203  

DD208  

DD206  

DDLM20  

DD 137  

(3) 2300 (2) 8200 (2) 36000

EMBODIMENTS Embodiment 1

A compound having the formula:

wherein, W is O or S; Ring A is independently substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl; Ring B isindependently substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; L¹ and L² are independently abond, substituted or unsubstituted (C₁-C₅) alkylene, or substituted orunsubstituted 2 to 5 membered heteroalkylene; R¹ and R² areindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃,—OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted(C₃-C₆) cycloalkyl, or substituted or unsubstituted 3 to 6 memberedheterocycloalkyl; R¹ and R² may optionally be joined to form asubstituted or unsubstituted 3 to 6 membered heterocycloalkyl orsubstituted or unsubstituted 5 to 6 membered heteroaryl; L¹ and R¹ mayoptionally be joined to form a substituted or unsubstituted 4 to 8membered heterocycloalkyl; L¹ and R² may optionally be joined to form asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl; L³ is abond, —O—, —N(R⁶)—, or —CH₂—; R⁵ is hydrogen, —CF₃, —CN, —COOH, —CONH₂,—CHF₂, —CH₂F, substituted or unsubstituted (C₁-C₅) alkyl, or substitutedor unsubstituted 2 to 5 membered heteroalkyl; and R⁶ is hydrogen, —CF₃,—CN, —COOH, —CONH₂, —CHF₂, —CH₂F, substituted or unsubstituted (C₁-C₅)alkyl, or substituted or unsubstituted 2 to 5 membered heteroalkyl.

Embodiment 2

The compound of embodiment 1, having the formula:

Embodiment 3

The compound of embodiment 1, having the formula:

Embodiment 4

The compound of one of embodiments 1 to 3, wherein Ring A is substitutedor unsubstituted (C₆-C₁₀) aryl or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment 5

The compound of one of embodiments 1 to 3, wherein Ring A isR³-substituted or unsubstituted (C₆-C₁₀) aryl or R³-substituted orunsubstituted 5 to 10 membered heteroaryl; R³ is independently hydrogen,halogen, —CX₃, —CN, —SO_(n)R¹⁰, —SO_(v)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸,—NHC═(O)NHNR⁷R⁸, —NHC═(O)NR⁷R⁸, —N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹,—C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂,—CH₂X, —OCX₃, —OCHX₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; Twoadjacent R³ substituents may optionally be joined to form a substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R⁷, R⁸, R⁹, and R¹⁰ are independentlyhydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁷ and R⁸ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; m and v are independently 1 or 2; n is independently aninteger from 0 to 4; X is independently —Cl, —Br, —I, or —F.

Embodiment 6

The compound of embodiment 5, wherein Ring A is R³-substituted orunsubstituted (C₆-C₁₀) aryl.

Embodiment 7

The compound of embodiment 5, wherein Ring A is R³-substituted orunsubstituted phenyl.

Embodiment 8

The compound of one of embodiments 5 to 7, wherein R³ is independentlyhydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂,substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl.

Embodiment 9

The compound of one of embodiments 5 to 7, wherein R³ is —OH.

Embodiment 10

The compound of one of embodiments 1 to 9, having the formula:

wherein R^(3A), R^(3B), and R^(3C) are independently hydrogen, halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.

Embodiment 11

The compound of one of embodiments 1 to 9, having the formula:

wherein R³ ishalogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.

Embodiment 12

The compound of embodiment 11, wherein R³ is —OH.

Embodiment 13

The compound of one of embodiments 1 to 9, having the formula:

wherein R^(3A), R^(3B), and R^(3C) are independentlyhalogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl; R^(3D) is hydrogen, halogen, —CF₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂,—CH₂F, OCF₃, —OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl, orsubstituted or unsubstituted 2 to 5 membered heteroalkyl; R^(3E) ishydrogen halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl; and z is an integer between 0 and 3.

Embodiment 14

The compound of embodiment 13, wherein R^(3D) and R^(3E) areindependently unsubstituted (C₁-C₅) alkyl.

Embodiment 15

The compound of embodiment 13, wherein R^(3D) and R^(3E) areindependently unsubstituted (C₁-C₃) alkyl.

Embodiment 16

The compound of embodiment 13, wherein R^(3D) and R^(3E) areindependently unsubstituted (C₁-C₂) alkyl.

Embodiment 17

The compound of embodiment 13, wherein R^(3D) and R^(3E) areindependently unsubstituted methyl.

Embodiment 18

The compound of embodiment 13, having the formula:

Embodiment 19

The compound of embodiment 18, wherein R^(3A) is —OH.

Embodiment 20

The compound of embodiment 5, wherein Ring A is unsubstituted phenyl.

Embodiment 21

The compound of one of embodiments 1 to 20, wherein Ring B issubstituted or unsubstituted (C₃-C₁₀) cycloalkyl or substituted orunsubstituted 3 to 10 membered heterocycloalkyl, substituted orunsubstituted (C₆-C₁₀) aryl, or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment 22

The compound of one of embodiments 1 to 20, wherein Ring B isR⁴-substituted or unsubstituted (C₃-C₁₀) cycloalkyl, R⁴-substituted orunsubstituted 5 to 10 membered heterocycloalkyl, R⁴-substituted orunsubstituted (C₆-C₁₀) aryl, or R⁴-substituted or unsubstituted 5 to 10membered heteroaryl; R⁴ is independently oxo,

halogen, —CX^(a) ₃, —CN, —SO_(n1)R¹⁴, —SO_(v1)NR¹¹R¹², —NHNR¹¹R¹²,—ONR¹¹R¹², —NHC═(O)NHNR¹¹R¹², —NHC═(O)NR¹¹R¹², —N(O)_(m1), —NR¹¹R¹²,—C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴, NRSO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)OR¹³, —NR¹¹OR¹³, —CHX₂, —CH₂X, —OCX₃, —OCHX₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R⁴ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹, R¹², R¹³, and R¹⁴ areindependently hydrogen,halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R¹¹ and R¹² substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; m1 and v1 are independently 1 or 2; n1 is independently aninteger from 0 to 4; X^(a) is independently —Cl, —Br, —I, or —F.

Embodiment 23

The compound of embodiment 22, wherein Ring B is R⁴-substituted orunsubstituted (C₃-C₁₀) cycloalkyl.

Embodiment 24

The compound of embodiment 22, wherein Ring B is R⁴-substituted orunsubstituted 3 to 10 membered heterocycloalkyl.

Embodiment 25

The compound of embodiment 22, wherein Ring B is R⁴-substituted orunsubstituted (C₆-C₁₀) aryl.

Embodiment 26

The compound of embodiment 22, wherein Ring B is R⁴-substituted orunsubstituted 5 to 10 membered heteroaryl.

Embodiment 27

The compound of embodiment 22, wherein Ring B is R⁴-substituted orunsubstituted thienyl, R⁴-substituted or unsubstituted phenyl,R⁴-substituted or unsubstituted benzothienyl, R⁴-substituted orunsubstituted naphthyl, R⁴-substituted or unsubstituted benzofuranyl,R⁴-substituted or unsubstituted furanyl, R⁴-substituted or unsubstitutedpyrrolyl, or R⁴-substituted or unsubstituted 2,3-dihydro-1H-indenyl.

Embodiment 28

The compound of one of embodiments 1 to 3, wherein Ring A isunsubstituted phenyl and Ring B is unsubstituted thienyl; Ring A ispara-hydroxy substituted phenyl and Ring B is unsubstituted thienyl;Ring A is para-hydroxy substituted phenyl and Ring B is unsubstitutedphenyl; Ring A is para-hydroxy substituted phenyl and Ring B isunsubstituted benzothienyl; Ring A is para-hydroxy substituted phenyland Ring B is para-methyl substituted phenyl; Ring A is 2-hydroxypyridin-4-yl and Ring B is unsubstituted thienyl; Ring A is 2-hydroxypyridin-5-yl and Ring B is unsubstituted thienyl; Ring A is para-hydroxysubstituted phenyl and Ring B is unsubstituted napththyl; or Ring A ispara-hydroxy substituted phenyl and Ring B is unsubstituted2,3-dihydro-1H-indenyl.

Embodiment 29

The compound of one of embodiments 22 to 28, wherein R⁴ is independentlyhalogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.

Embodiment 30

The compound of one of embodiments 22 to 28, wherein R⁴ is methyl.

Embodiment 31

The compound of embodiment 22, wherein Ring B is unsubstituted phenyl.

Embodiment 32

The compound of one of embodiments 1 to 31, wherein L¹ is substituted orunsubstituted (C₁-C₅) alkylene.

Embodiment 33

The compound of one of embodiments 1 to 31, wherein L¹ is substituted orunsubstituted 2 to 5 membered heteroalkylene.

Embodiment 34

The compound of one of embodiments 1 to 31, wherein L¹ is unsubstituted(C₁-C₃) alkylene.

Embodiment 35

The compound of one of embodiments 1 to 31, wherein L¹ isR⁹⁶-substituted or unsubstituted C₁-C₅ alkylene, R⁹⁶-substituted orunsubstituted 2 to 5 membered heteroalkylene; R⁹⁶ is independently oxo,

halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —OCH₂X⁹⁶, —OCHX⁹⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹⁶ ₃, —OCHX⁹⁶ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X⁹⁶ is halogen.

Embodiment 36

The compound of one of embodiments 1 to 31, wherein L¹ isR⁹⁶-substituted or unsubstituted C₁-C₅ alkylene; R⁹⁶ is independentlyoxo,

halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —OCH₂X⁹⁶, —OCHX⁹⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹⁶ ₃, —OCHX⁹⁶ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X⁹⁶ is halogen.

Embodiment 37

The compound of one of embodiments 1 to 31, wherein L¹ isR⁹⁶-substituted or unsubstituted C₁-C₃ alkylene; R⁹⁶ is independentlyoxo,

halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —OCH₂X⁹⁶, —OCHX⁹⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹⁶ ₃, —OCHX⁹⁶ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X⁹⁶ is halogen.

Embodiment 38

The compound of one of embodiments 1 to 31, wherein L¹ isR⁹⁶-substituted or unsubstituted methylene; R⁹⁶ is independently oxo,

halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —OCH₂X⁹⁶, —OCHX⁹⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹⁶ ₃, —OCHX⁹⁶ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X⁹⁶ is halogen.

Embodiment 39

The compound of one of embodiments 1 to 31, wherein L¹ isR⁹⁶-substituted or unsubstituted 2 to 5 membered heteroalkylene; R⁹⁶ isindependently oxo,

halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —OCH₂X⁹⁶, —OCHX⁹⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹⁶ ₃, —OCHX⁹⁶ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X⁹⁶ is halogen.

Embodiment 40

The compound of one of embodiments 1 to 31, wherein L¹ isR⁹⁶-substituted or unsubstituted 2 to 3 membered heteroalkylene; R⁹⁶ isindependently oxo,

halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —OCH₂X⁹⁶, —OCHX⁹⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹⁶ ₃, —OCHX⁹⁶ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X⁹⁶ is halogen.

Embodiment 41

The compound of one of embodiments 1 to 31, wherein L¹ is unsubstitutedmethylene.

Embodiment 42

The compound of one of embodiments 1 to 41, wherein R¹ is unsubstituted(C₁-C₃) alkyl.

Embodiment 43

The compound of one of embodiments 1 to 41, wherein R¹ is unsubstituted(C₁-C₂) alkyl.

Embodiment 44

The compound of one of embodiments 1 to 41, wherein R¹ is independentlyhydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₆)cycloalkyl, or substituted or unsubstituted 3 to 6 memberedheterocycloalkyl.

Embodiment 45

The compound of one of embodiments 1 to 41, wherein R¹ is independentlyhalogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

Embodiment 46

The compound of one of embodiments 1 to 41, wherein R¹ is independentlyhalogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, R³⁰-substituted orunsubstituted (C₁-C₅) alkyl, R³⁰-substituted or unsubstituted 2 to 5membered heteroalkyl, R³⁰-substituted or unsubstituted (C₃-C₆)cycloalkyl, or R³⁰-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl; R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³⁰ ₃, —OCHX³⁰ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X³⁰ is halogen.

Embodiment 47

The compound of one of embodiments 1 to 41, wherein R¹ isR³⁰-substituted or unsubstituted (C₁-C₃) alkyl or R³⁰-substituted orunsubstituted 2 to 3 membered heteroalkyl; R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHOH, —OCX³⁰ ₃, —OCHX³⁰ ₂,substituted or unsubstituted (C₁-C₃) alkyl, substituted or unsubstituted2 to 3 membered heteroalkyl, or substituted or unsubstitutedcyclopropyl; and X³⁰ is halogen.

Embodiment 48

The compound of one of embodiments 1 to 41, wherein R¹ isR³⁰-substituted or unsubstituted (C₁-C₂) alkyl; R³⁰ is independentlyhalogen, —OH, —NH₂, —SH, substituted or unsubstituted (C₁-C₃) alkyl,substituted or unsubstituted 2 to 3 membered heteroalkyl, or substitutedor unsubstituted cyclopropyl; and X³⁰ is halogen.

Embodiment 49

The compound of one of embodiments 1 to 41, wherein R¹ is unsubstitutedmethyl.

Embodiment 50

The compound of one of embodiments 1 to 49, wherein R² is unsubstituted(C₁-C₃) alkyl.

Embodiment 51

The compound of one of embodiments 1 to 49, wherein R² is unsubstituted(C₁-C₂) alkyl.

Embodiment 52

The compound of one of embodiments 1 to 49, wherein R² is independentlyhydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₆)cycloalkyl, or substituted or unsubstituted 3 to 6 memberedheterocycloalkyl.

Embodiment 53

The compound of one of embodiments 1 to 49, wherein R² is independentlyhalogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

Embodiment 54

The compound of one of embodiments 1 to 49, wherein R² is independentlyhalogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, R³³-substituted orunsubstituted (C₁-C₅) alkyl, R³³-substituted or unsubstituted 2 to 5membered heteroalkyl, R³³-substituted or unsubstituted (C₃-C₆)cycloalkyl, or R³³-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl; R³³ is independently oxo,

halogen, —CX³³ ₃, —CHX³⁰ ₂, —OCH₂X³³, —OCHX³³ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³³ ₃, —OCHX³³ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X³³ is halogen.

Embodiment 55

The compound of one of embodiments 1 to 49, wherein R² isR³³-substituted or unsubstituted (C₁-C₃) alkyl or R³³-substituted orunsubstituted 2 to 3 membered heteroalkyl; R³³ is independently oxo,

halogen, —CX³³ ₃, —CHX³³ ₂, —OCH₂X³³, —OCHX³³ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHOH, —OCX³³ ₃, —OCHX³³ ₂,substituted or unsubstituted (C₁-C₃) alkyl, substituted or unsubstituted2 to 3 membered heteroalkyl, or substituted or unsubstitutedcyclopropyl; and X³³ is halogen.

Embodiment 56

The compound of one of embodiments 1 to 49, wherein R² isR³³-substituted or unsubstituted (C₁-C₂) alkyl; R³³ is independentlyhalogen, —OH, —NH₂, —SH, substituted or unsubstituted (C₁-C₃) alkyl,substituted or unsubstituted 2 to 3 membered heteroalkyl, or substitutedor unsubstituted cyclopropyl; and X³³ is halogen.

Embodiment 57

The compound of one of embodiments 1 to 49, wherein R² is unsubstitutedmethyl.

Embodiment 58

The compound of one of embodiments 1 to 31, wherein L¹ and R¹ are joinedto form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.

Embodiment 59

The compound of one of embodiments 1 to 31, wherein L¹ and R¹ are joinedto form a R³⁰-substituted or unsubstituted 4 to 8 memberedheterocycloalkyl; R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³⁰ ₃, —OCHX³⁰ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X³⁰ is halogen.

Embodiment 60

The compound of one of embodiments 1 to 31, wherein L¹ and R¹ are joinedto form a R³⁰-substituted or unsubstituted 4 to 8 memberedheterocycloalkyl; R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³⁰ ₃, —OCHX³⁰ ₂,substituted or unsubstituted (C₁-C₃) alkyl, or substituted orunsubstituted 2 to 3 membered heteroalkyl; and X³⁰ is halogen.

Embodiment 61

The compound of one of embodiments 1 to 31, wherein L¹ and R¹ are joinedto form a R³⁰-substituted or unsubstituted 4 to 8 memberedheterocycloalkyl; R³⁰ is independently oxo, halogen, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, substituted or unsubstituted (C₁-C₃) alkyl, orsubstituted or unsubstituted 2 to 3 membered heteroalkyl; and X³⁰ ishalogen.

Embodiment 62

The compound of one of embodiments 1 to 31, wherein L¹ and R² are joinedto form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl.

Embodiment 63

The compound of one of embodiments 1 to 31, wherein L¹ and R² are joinedto form a R³³-substituted or unsubstituted 4 to 8 memberedheterocycloalkyl; R³³ is independently oxo,

halogen, —CX³³ ₃, —CHX³³ ₂, —OCH₂X³³, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³³ ₃, —OCHX³³ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X³³ is halogen.

Embodiment 64

The compound of one of embodiments 1 to 31, wherein L¹ and R² are joinedto form a R³³-substituted or unsubstituted 4 to 8 memberedheterocycloalkyl; R³³ is independently oxo,

halogen, —CX³³ ₃, —CHX³³ ₂, —OCH₂X³³, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³³ ₃, —OCHX³³ ₂,substituted or unsubstituted (C₁-C₃) alkyl, or substituted orunsubstituted 2 to 3 membered heteroalkyl; and X³³ is halogen.

Embodiment 65

The compound of one of embodiments 1 to 31, wherein L¹ and R² are joinedto form a R³³-substituted or unsubstituted 4 to 8 memberedheterocycloalkyl; R³³ is independently oxo, halogen, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, substituted or unsubstituted (C₁-C₃) alkyl, orsubstituted or unsubstituted 2 to 3 membered heteroalkyl; and X³³ ishalogen.

Embodiment 66

The compound of one of embodiments 1 to 31, wherein R¹ and R² are joinedto form a substituted or unsubstituted 3 to 6 membered heterocycloalkylor substituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment 67

The compound of one of embodiments 1 to 31, wherein R¹ and R² are joinedto form a substituted or unsubstituted 3 to 6 membered heterocycloalkyl.

Embodiment 68

The compound of one of embodiments 1 to 31, wherein R¹ and R² are joinedto form a R³⁰-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl; R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³⁰ ₃, —OCHX³⁰ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X³⁰ is halogen.

Embodiment 69

The compound of one of embodiments 1 to 31, wherein R¹ and R² are joinedto form a R³⁰-substituted or unsubstituted 3 to 6 memberedheterocycloalkyl; R³⁰ is independently oxo,

halogen, —CX³⁰ ₃, —CHX³⁰ ₂, —OCH₂X³⁰, —OCHX³⁰ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX³⁰ ₃, —OCHX³⁰ ₂,substituted or unsubstituted (C₁-C₃) alkyl, or substituted orunsubstituted 2 to 3 membered heteroalkyl; and X³⁰ is halogen.

Embodiment 70

The compound of one of embodiments 1 to 69, wherein R⁵ is substituted orunsubstituted (C₁-C₅) alkyl or substituted or unsubstituted 2 to 5membered heteroalkyl.

Embodiment 71

The compound of one of embodiments 1 to 69, wherein R⁵ is substituted orunsubstituted (C₁-C₅) alkyl.

Embodiment 72

The compound of one of embodiments 1 to 69, wherein R⁵ is unsubstituted(C₁-C₅) alkyl.

Embodiment 73

The compound of one of embodiments 1 to 69, wherein R⁵ is unsubstituted(C₁-C₃) alkyl.

Embodiment 74

The compound of one of embodiments 1 to 69, wherein R⁵ is unsubstitutedmethyl.

Embodiment 75

The compound of one of embodiments 1 to 69, wherein R⁵ is hydrogen.

Embodiment 76

The compound of one of embodiments 1 to 75, wherein W is O.

Embodiment 77

The compound of one of embodiments 1 to 75, wherein W is S.

Embodiment 78

The compound of one of embodiments 1 to 77, wherein L³ is —N(R⁶)—.

Embodiment 79

The compound of one of embodiments 1 to 78, wherein R⁶ is hydrogen.

Embodiment 80

The compound of one of embodiments 1 to 78, wherein R⁶ is substituted orunsubstituted (C₁-C₅) alkyl or substituted or unsubstituted 2 to 5membered heteroalkyl.

Embodiment 81

The compound of one of embodiments 1 to 78, wherein R⁶ is substituted orunsubstituted (C₁-C₅) alkyl.

Embodiment 82

The compound of one of embodiments 1 to 78, wherein R⁶ is unsubstituted(C₁-C₅) alkyl.

Embodiment 83

The compound of one of embodiments 1 to 78, wherein R⁶ is unsubstituted(C₁-C₃) alkyl.

Embodiment 84

The compound of one of embodiments 1 to 78, wherein R⁶ is unsubstitutedmethyl.

Embodiment 85

The compound of one of embodiments 1 to 77, wherein L³ is a bond.

Embodiment 86

The compound of one of embodiments 1 to 77, wherein L³ is —O—.

Embodiment 87

The compound of one of embodiments 1 to 77, wherein L³ is —CH₂—.

Embodiment 88

The compound of one of embodiments 1 to 87, wherein L² is a bond.

Embodiment 89

The compound of one of embodiments 1 to 87, wherein L² is substituted orunsubstituted 2 to 5 membered heteroalkylene.

Embodiment 90

The compound of one of embodiments 1 to 87, wherein L² is unsubstituted2 to 5 membered heteroalkylene.

Embodiment 91

The compound of one of embodiments 1 to 87, wherein L² is substituted orunsubstituted (C₁-C₅) alkylene.

Embodiment 92

The compound of one of embodiments 1 to 87, wherein L² is unsubstituted(C₁-C₅) alkylene.

Embodiment 93

The compound of one of embodiments 1 to 87, wherein L² is unsubstituted(C₁-C₄) alkylene.

Embodiment 94

The compound of one of embodiments 1 to 87, wherein L² is unsubstituted(C₁-C₃) alkylene.

Embodiment 95

The compound of one of embodiments 1 to 87, wherein L² is unsubstituted(C₁-C₂) alkylene.

Embodiment 96

The compound of one of embodiments 1 to 84, having the formula:

wherein d is an integer between 0 and 3.

Embodiment 97

The compound of one of embodiments 1 to 84, having the formula:

wherein d is an integer between 0 and 3.

Embodiment 98

The compound of one of embodiments 1 to 84, having the formula:

wherein d is an integer between 0 and 3.

Embodiment 99

The compound of one of embodiments 1 to 84, having the formula:

wherein d is an integer between 0 and 3.

Embodiment 100

The compound of one of embodiments 1 to 84, having the formula:

wherein d is an integer between 0 and 3.

Embodiment 101

The compound of one of embodiments 1 to 84, having the formula:

wherein d is an integer between 0 and 3.

Embodiment 102

The compound of embodiment 1, having the formula:

wherein Ring B is a substituted or unsubstituted phenyl or substitutedor unsubstituted 5 to 6 membered heteroaryl; R³ is halogen, —OH, or—NH₂; R^(99a) is substituted or unsubstituted (C₁-C₃) alkyl; and R^(99b)is hydrogen or substituted or unsubstituted (C₁-C₃) alkyl.

Embodiment 103

The compound of embodiment 102, wherein Ring B is an unsubstitutedphenyl.

Embodiment 104

The compound of embodiment 102, wherein Ring B is an unsubstituted 5 to6 membered heteroaryl.

Embodiment 105

The compound of embodiment 102, wherein Ring B is an unsubstituted3-thienyl.

Embodiment 106

The compound of one of embodiments 102 to 105, wherein R³ is —OH.

Embodiment 107

The compound of one of embodiments 102 to 106, wherein R^(99a) isunsubstituted methyl.

Embodiment 108

The compound of one of embodiments 102 to 107, wherein R^(99b) ishydrogen.

Embodiment 109

The compound of one of embodiments 102 to 107, wherein R^(99b) isunsubstituted methyl.

Embodiment 110

The compound of one of embodiments 102 to 109, wherein R¹ and R² areunsubstituted methyl.

Embodiment 111

The compound of one of embodiments 102 to 110, having the formula

Embodiment 112

The compound of one of embodiments 102 to 110, having the formula

Embodiment 113

The compound of one of embodiments 102 to 110, having the formula

Embodiment 114

The compound of one of embodiments 102 to 110, having the formula

Embodiment 115

The compound of embodiment 1, having the formula:

wherein Ring B is a substituted or unsubstituted phenyl or substitutedor unsubstituted 5 to 6 membered heteroaryl; R^(3A) is halogen, —OH, or—NH₂; R^(3D) is unsubstituted (C₁-C₂) alkyl; R^(3E) is unsubstituted(C₁-C₂) alkyl; R^(99a) is hydrogen or substituted or unsubstituted(C₁-C₃) alkyl; and R^(99b) is substituted or unsubstituted (C₁-C₃)alkyl.

Embodiment 116

The compound of embodiment 115, wherein Ring B is an unsubstitutedphenyl.

Embodiment 117

The compound of embodiment 115, wherein Ring B is an unsubstituted 5 to6 membered heteroaryl.

Embodiment 118

The compound of embodiment 115, wherein Ring B is an unsubstituted3-thienyl.

Embodiment 119

The compound of one of embodiments 115 to 118, wherein R^(3A) is —OH.

Embodiment 120

The compound of one of embodiments 115 to 119, wherein R^(99b) isunsubstituted methyl.

Embodiment 121

The compound of one of embodiments 115 to 120, wherein R^(99a) ishydrogen.

Embodiment 122

The compound of one of embodiments 115 to 120, wherein R^(99a) isunsubstituted methyl.

Embodiment 123

The compound of one of embodiments 115 to 122, wherein R¹ and R² areunsubstituted methyl.

Embodiment 124

The compound of one of embodiments 115 to 123, wherein R^(3D) isunsubstituted methyl.

Embodiment 125

The compound of one of embodiments 115 to 124, wherein R^(3E) isunsubstituted methyl.

Embodiment 126

The compound of embodiment 1, having the formula:

Embodiment 127

The compound of embodiment 1, having the formula:

Embodiment 128

The compound of one of embodiments 1 to 127, wherein the compound is not

Embodiment 129

A compound of one of embodiments 1 to 128 having a lower bindingaffinity for the mu opioid receptor than for the kappa opioid receptor.

Embodiment 130

A compound of one of embodiments 1 to 128 having greater than 10-foldlower binding affinity for the mu opioid receptor than for the kappaopioid receptor.

Embodiment 131

A compound of one of embodiments 1 to 128 having greater than 100-foldlower binding affinity for the mu opioid receptor than for the kappaopioid receptor.

Embodiment 132

A compound of one of embodiments 1 to 131 having a lower bindingaffinity for the mu opioid receptor than for the delta opioid receptor.

Embodiment 133

A compound of one of embodiments 1 to 131 having greater than 10-foldlower binding affinity for the mu opioid receptor than for the deltaopioid receptor.

Embodiment 134

A compound of one of embodiments 1 to 131 having greater than 100-foldlower binding affinity for the mu opioid receptor than for the deltaopioid receptor.

Embodiment 135

A compound of one of embodiments 1 to 134 having a lower bindingaffinity for the mu opioid receptor than for the nociceptin receptor.

Embodiment 136

A compound of one of embodiments 1 to 134 having greater than 10-foldlower binding affinity for the mu opioid receptor than for thenociceptin receptor.

Embodiment 137

A compound of one of embodiments 1 to 134 having greater than 100-foldlower binding affinity for the mu opioid receptor than for thenociceptin receptor.

Embodiment 138

A compound of one of embodiments 1 to 137 having a lower addictionpotential than other medically used opioids.

Embodiment 139

A compound of one of embodiments 1 to 137 having a lower addictionpotential than other medically used opiate.

Embodiment 140

A compound of one of embodiments 1 to 137 having a lower addictionpotential than morphine.

Embodiment 141

A compound of one of embodiments 1 to 137 having a lower addictionpotential than heroin.

Embodiment 142

A compound of one of embodiments 1 to 137 having a lower addictionpotential than oxycodone.

Embodiment 143

A compound of one of embodiments 1 to 137 having a lower addictionpotential than fentanyl.

Embodiment 144

A compound of one of embodiments 1 to 137 having a lower addictionpotential than hydrocodone.

Embodiment 145

A compound of one of embodiments 1 to 137 having a lower addictionpotential than hydromorphone.

Embodiment 146

A compound of one of embodiments 1 to 137 having a lower addictionpotential than methadone.

Embodiment 147

A compound of one of embodiments 1 to 137 having a lower addictionpotential than oxymorphone.

Embodiment 148

A pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of one of embodiments 1 to 147.

Embodiment 149

A method of treating pain in a subject in need of said treatment, saidmethod comprising administering an effective amount of a compound of oneof embodiments 1 to 12, 20 to 114, 126, and 128 to 147, to said subject.

Embodiment 150

The method of embodiment 149, wherein said pain is acute pain.

Embodiment 151

The method of embodiment 149, wherein pain is chronic pain.

Embodiment 152

The method of one of embodiments 149 to 151, wherein said method doesnot comprise an increased risk of respiratory depression.

Embodiment 153

The method of one of embodiments 149 to 151, wherein said method doesnot comprise respiratory depression.

Embodiment 154

The method of one of embodiments 149 to 151, wherein said method doesnot comprise an increased risk of constipation.

Embodiment 155

The method of one of embodiments 149 to 151, wherein said method doesnot comprise constipation.

Embodiment 156

A method of treating opioid overdose in a subject in need of saidtreatment, said method comprising administering an effective amount of acompound of one of embodiments 1 to 8, 10, 13 to 101, 115 to 125, and127 to 147, to said subject.

Embodiment 157

A method of treating addiction in a subject in need of said treatment,said method comprising administering an effective amount compound of oneof embodiments 1 to 12, 30 to 114, 126, and 128 to 147, to said subject.

Embodiment 158

The method of embodiment 157, wherein said addiction is opioidaddiction.

Embodiment 159

The method of embodiment 157, wherein said addiction is nicotineaddiction.

Embodiment 160

The method of one of embodiments 157 to 159, wherein said method doesnot comprise an increased risk of respiratory depression.

Embodiment 161

The method of one of embodiments 157 to 159, wherein said method doesnot comprise respiratory depression.

Embodiment 162

The method of one of embodiments 157 to 159, wherein said method doesnot comprise an increased risk of constipation.

Embodiment 163

The method of one of embodiments 157 to 159, wherein said method doesnot comprise constipation.

Embodiment 164

A method of treating a psychiatric disorder in a subject in need of saidtreatment, said method comprising administering an effective amount of acompound of one of embodiments 1 to 12, 20 to 114, 126, and 128 to 147,to said subject.

Embodiment 165

The method of embodiment 164, wherein said psychiatric disorder isdepression.

Embodiment 166

The method of embodiment 164, wherein said psychiatric disorder isanxiety.

Embodiment 167

The method of one of embodiments 164 to 166, wherein said method doesnot comprise an increased risk of respiratory depression.

Embodiment 168

The method of one of embodiments 164 to 166, wherein said method doesnot comprise respiratory depression.

Embodiment 169

The method of one of embodiments 164 to 166, wherein said method doesnot comprise an increased risk of constipation.

Embodiment 170

The method of one of embodiments 164 to 166, wherein said method doesnot comprise constipation.

Embodiment 171

A method of modulating the activity of an opioid receptor protein, saidmethod comprising contacting said opioid receptor protein with aneffective amount of a compound of one of embodiments 1 to 147.

Embodiment 172

The method of embodiment 171, wherein said opioid receptor is a human muopioid receptor.

Embodiment 173

The method of one of embodiments 171 to 172, wherein modulating isactivating.

Embodiment 174

The method of one of embodiments 171 to 172, wherein modulating isinhibiting.

Embodiment 175

The method of one of embodiments 171 to 174, wherein said method doesnot comprise modulating arrestin function.

Embodiment 176

The method of one of embodiments 171 to 175, wherein said method doesnot comprise modulating the activity of a human kappa opioid receptor.

Embodiment 177

The method of one of embodiments 171 to 176, wherein said method doesnot comprise modulating the activity of a human delta opioid receptor.

Embodiment 178

The method of one of embodiments 171 to 177, wherein said method doesnot comprise modulating the activity of a human nociceptin receptor.

Additional Embodiments Embodiment N1

A compound having the formula:

wherein, W is O or S; Ring A is substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl; Ring B is substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; L¹ and L² are independently a bond, substituted orunsubstituted (C₁-C₅) alkylene, or substituted or unsubstituted 2 to 5membered heteroalkylene; R¹ and R² are independently hydrogen, halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl; R¹ andR² may optionally be joined to form a substituted or unsubstituted 3 to6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6membered heteroaryl; L¹ and R¹ may optionally be joined to form asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl; L¹ and R²may optionally be joined to form a substituted or unsubstituted 4 to 8membered heterocycloalkyl; L³ is a bond, —O—, —N(R⁶)—, or —CH₂—; R⁵ ishydrogen, —CF₃, —CN, —COOH, —CONH₂, —CHF₂, —CH₂F, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl; and R⁶ ishydrogen, —CF₃, —CN, —COOH, —CONH₂, —CHF₂, —CH₂F, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.

Embodiment N2

The compound of embodiment N1, wherein Ring A is substituted orunsubstituted (C₆-C₁₀) aryl or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment N3

The compound of embodiment N1, wherein Ring A is R³-substituted orunsubstituted (C₆-C₁₀) aryl or R³-substituted or unsubstituted 5 to 10membered heteroaryl; R³ is independently hydrogen, halogen, —CX₃, —CN,—SO_(n)R¹, —SO_(v)NR⁷R⁸, —NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸,—NHC═(O)NR⁷R⁸, —N(O)_(m), —NR⁷R⁸, —C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰,—NR⁷SO₂R, —NR⁷C═(O)R⁹, —NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂, —CH₂X, —OCX₃,—OCHX₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; two adjacent R³ substituentsmay optionally be joined to form a substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁷,R⁸, R⁹, and R¹⁰ are independently hydrogen, halogen, —CF₃, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂,—CH₂F, OCF₃, —OCHF₂, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁷ andR⁸ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl orsubstituted or unsubstituted heteroaryl; m and v are independently 1 or2; n is independently an integer from 0 to 4; and X is independently—Cl, —Br, —I, or —F.

Embodiment N4

The compound of embodiment N3, wherein Ring A is R³-substituted orunsubstituted phenyl.

Embodiment N5

The compound of embodiment N3 or N4, wherein R³ is independentlyhydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂,substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl.

Embodiment N6

The compound of any one of embodiments N1 to N5, having the formula:

whereinR³ is halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.

Embodiment N7

The compound of any one of embodiments N1 to N5, having the formula:

wherein R^(3A), R^(3B), and R^(3C) are independently halogen, —CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl,or substituted or unsubstituted 2 to 5 membered heteroalkyl;R^(3D) is hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂,substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl;R^(3E) is hydrogen halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂,substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl.

Embodiment N8

The compound of embodiment N7, wherein R^(3D) and R^(3E) areindependently unsubstituted (C₁-C₃) alkyl.

Embodiment N9

The compound of embodiment N7, wherein R^(3D) and R^(3E) areindependently unsubstituted methyl.

Embodiment N10

The compound of any one of embodiments N1 to N5, having the formula:

Embodiment N11

The compound of any one of embodiments N1 to N10, wherein Ring B issubstituted or unsubstituted (C₃-C₁₀) cycloalkyl or substituted orunsubstituted 3 to 10 membered heterocycloalkyl, substituted orunsubstituted (C₆-C₁₀) aryl, or substituted or unsubstituted 5 to 10membered heteroaryl.

Embodiment N12

The compound of any one of embodiments N1 to N10, wherein Ring B isR⁴-substituted or unsubstituted (C₃-C₁₀) cycloalkyl, R⁴-substituted orunsubstituted 5 to 10 membered heterocycloalkyl, R⁴-substituted orunsubstituted (C₆-C₁₀) aryl, or R⁴-substituted or unsubstituted 5 to 10membered heteroaryl; R⁴ is independently oxo,

halogen, —CX^(a) ₃, —CN, —SO_(n1)R¹⁴, —SO_(v1)NR¹¹R¹², —NHNR¹¹R¹²,—ONR¹¹R¹², —NHC═(O)NHNR¹¹R¹², NHC═(O)NR¹¹R¹², —N(O)_(m1), —NR¹¹R¹²,—C(O)R¹³, —C(O)—OR¹³, —C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³,—NR¹¹C(O)OR¹³, —NR¹¹OR¹³, —CHX₂, —CH₂X, —OCX₃, —OCHX₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; two adjacent R⁴ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹, R¹², R¹³, and R¹⁴ areindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃,—OCHF₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹ and R¹² substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; m1 and v1 are independently 1 or 2; n1 is independently aninteger from 0 to 4; andX^(a) is independently —Cl, —Br, —I, or —F.

Embodiment N13

The compound of any one of embodiments N1 to N10, wherein Ring B isR⁴-substituted or unsubstituted thienyl, R⁴-substituted or unsubstitutedphenyl, R⁴-substituted or unsubstituted benzothienyl, R⁴-substituted orunsubstituted naphthyl, R⁴-substituted or unsubstituted benzofuranyl,R⁴-substituted or unsubstituted furanyl, R⁴-substituted or unsubstitutedpyrrolyl, or R⁴-substituted or unsubstituted 2,3-dihydro-1H-indenyl.

Embodiment N14

The compound of any one of embodiments N1 to N10, wherein

Ring A is unsubstituted phenyl and Ring B is unsubstituted thienyl;Ring A is para-hydroxy substituted phenyl and Ring B is unsubstitutedthienyl;Ring A is para-hydroxy substituted phenyl and Ring B is unsubstitutedphenyl;Ring A is para-hydroxy substituted phenyl and Ring B is unsubstitutedbenzothienyl;Ring A is para-hydroxy substituted phenyl and Ring B is para-methylsubstituted phenyl;Ring A is 2-hydroxy pyridin-4-yl and Ring B is unsubstituted thienyl;Ring A is 2-hydroxy pyridin-5-yl and Ring B is unsubstituted thienyl;Ring A is para-hydroxy substituted phenyl and Ring B is unsubstitutednapththyl; orRing A is para-hydroxy substituted phenyl and Ring B is unsubstituted2,3-dihydro-1H-indenyl.

Embodiment N15

The compound of any one of embodiments N1 to N10, wherein Ring B isunsubstituted phenyl.

Embodiment N16

The compound of any one of embodiments N1 to N15, wherein L¹ isR⁹⁶-substituted or unsubstituted C₁-C₅ alkylene, R⁹⁶-substituted orunsubstituted 2 to 5 membered heteroalkylene; R⁹⁶ is independently oxo,

halogen, —CX⁹⁶ ₃, —CHX⁹⁶ ₂, —OCH₂X⁹⁶, —OCHX⁹⁶ ₂, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —S H, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCX⁹⁶ ₃, —OCHX⁹⁶ ₂,substituted or unsubstituted (C₁-C₅) alkyl, substituted or unsubstituted2 to 5 membered heteroalkyl, substituted or unsubstituted (C₃-C₅)cycloalkyl, substituted or unsubstituted 3 to 5 memberedheterocycloalkyl, substituted or unsubstituted phenyl, or substituted orunsubstituted 5 to 6 membered heteroaryl; and X⁹⁶ is halogen.

Embodiment N17

The compound of any one of embodiments N1 to N15, wherein L¹ isR⁹⁶-substituted or unsubstituted methylene.

Embodiment N18

The compound of any one of embodiments N1 to N17, wherein R¹ isunsubstituted (C₁-C₂) alkyl.

Embodiment N19

The compound of any one of embodiments N1 to N17, wherein R¹ isindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃,—OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted(C₃-C₆) cycloalkyl, or substituted or unsubstituted 3 to 6 memberedheterocycloalkyl.

Embodiment N20

The compound of any one of embodiments N1 to N19, wherein R² isunsubstituted (C₁-C₂) alkyl.

Embodiment N21

The compound of any one of embodiments N1 to N19, wherein R² isindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃,—OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl, substituted orunsubstituted 2 to 5 membered heteroalkyl, substituted or unsubstituted(C₃-C₆) cycloalkyl, or substituted or unsubstituted 3 to 6 memberedheterocycloalkyl.

Embodiment N22

The compound of any one of embodiments N1 to N17, wherein R¹ and R² arejoined to form a substituted or unsubstituted 3 to 6 memberedheterocycloalkyl or substituted or unsubstituted 5 to 6 memberedheteroaryl.

Embodiment N23

The compound of any one of embodiments N1 to N22, wherein R⁵ ishydrogen, substituted or unsubstituted (C₁-C₅) alkyl or substituted orunsubstituted 2 to 5 membered heteroalkyl.

Embodiment N24

The compound of any one of embodiments N1 to N23, wherein W is O.

Embodiment N25

The compound of any one of embodiments N1 to N24, wherein L³ is —N(R⁶)—.

Embodiment N26

The compound of any one of embodiments N1 to N25, wherein R⁶ ishydrogen, substituted or unsubstituted (C₁-C₅) alkyl or substituted orunsubstituted 2 to 5 membered heteroalkyl.

Embodiment N27

The compound of any one of embodiments N1 to N26, wherein L² issubstituted or unsubstituted (C₁-C₃) alkylene, or substituted orunsubstituted 2 to 5 membered heteroalkylene.

Embodiment N28

The compound of embodiment N1, having the formula:

wherein d is an integer between 0 and 3.

Embodiment N29

The compound of embodiment N1, having the formula:

R¹, R² wherein d is an integer between 0 and 3.

Embodiment N30

The compound of embodiment N1, having the formula:

wherein Ring B is a substituted or unsubstituted phenyl or substitutedor unsubstituted 5 to 6 membered heteroaryl; R³ is halogen, —OH, or—NH₂; R^(99a) is substituted or unsubstituted (C₁-C₃) alkyl; and R^(99b)is hydrogen or substituted or unsubstituted (C₁-C₃) alkyl.

Embodiment N31

The compound of any one of embodiments N1 to N30, wherein Ring B is anunsubstituted 3-thienyl.

Embodiment N32

The compound of embodiment N1, having the formula:

wherein Ring B is a substituted or unsubstituted phenyl or substitutedor unsubstituted 5 to 6 membered heteroaryl; R^(3A) is halogen, —OH, or—NH₂; R^(3D) is unsubstituted (C₁-C₂) alkyl; R^(3E) is unsubstituted(C₁-C₂) alkyl; R^(99a) is hydrogen or substituted or unsubstituted(C₁-C₃) alkyl; R^(99b) is substituted or unsubstituted (C₁-C₃) alkyl.

Embodiment N33

The compound of embodiment N1, having the formula:

Embodiment N34

The compound of embodiment N1, having the formula:

Embodiment N35

The compound of embodiment N1, wherein the compound is

Embodiment N36

The compound of any one of embodiments N1 to N35, having a higherbinding affinity for the mu opioid receptor than for the kappa opioidreceptor.

Embodiment N37

The compound of any one of embodiments N1 to N35, having a higherbinding affinity for the mu opioid receptor than for the delta opioidreceptor.

Embodiment N38

The compound of any one of embodiments N1 to N35, having a higherbinding affinity for the mu opioid receptor than for the nociceptinreceptor.

Embodiment N39

The compound of any one of embodiments N1 to N35, having a loweraddiction potential than other medically used opioids or opiates.

Embodiment N40

The compound of any one of embodiments N1 to N35, having a loweraddiction potential than morphine, heroin, oxycodone, fentanyl,hydrocodone, hydromorphone, methadone, or oxymorphone.

Embodiment N41

A pharmaceutical composition comprising a pharmaceutically acceptableexcipient and a compound of one of embodiments N1 to N40.

Embodiment N42

A method of treating pain in a subject in need of said treatment, saidmethod comprising administering an effective amount of a compound of oneof embodiments N1 to N6, N11 to N31, N33, or N35 to N40, to saidsubject.

Embodiment N43

The method of embodiment N42, wherein said method does not comprise anincreased risk of respiratory depression or constipation.

Embodiment N44

A method of treating opioid overdose in a subject in need of saidtreatment, said method comprising administering an effective amount of acompound of one of embodiments N1 to N5, N7 to N29, N32, or N34 to N40,to said subject.

Embodiment N45

A method of treating addiction in a subject in need of said treatment,said method comprising administering an effective amount compound of oneof embodiments N1 to N6, N11 to N31, N33, or N35 to N40, to saidsubject.

Embodiment N46

A method of treating a psychiatric disorder in a subject in need of saidtreatment, said method comprising administering an effective amount of acompound of one of embodiments N1 to N6, N11 to N31, N33, or N35 to N40,to said subject.

Embodiment N47

A method of modulating the activity of an opioid receptor protein, saidmethod comprising contacting said opioid receptor protein with aneffective amount of a compound of one of embodiments N1 to N40.

Embodiment N48

The method of embodiment N47, wherein said method does not comprisemodulating arrestin function.

Embodiment N49

The compound of embodiment 1, wherein the compound is not

1. A compound having the formula:

wherein, W is O or S; Ring A is independently substituted orunsubstituted aryl or substituted or unsubstituted heteroaryl; Ring B isindependently substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; L¹ and L² are independently abond or unsubstituted (C₁-C₅) alkylene; R¹ and R² are independentlyhydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, NHC═(O)NHNH₂, NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl; R¹ andR² may optionally be joined to form a substituted or unsubstituted 3 to6 membered heterocycloalkyl or substituted or unsubstituted 5 to 6membered heteroaryl; L¹ and R¹ may optionally be joined to form asubstituted or unsubstituted 4 to 8 membered heterocycloalkyl; L¹ and R²may optionally be joined to form a substituted or unsubstituted 4 to 8membered heterocycloalkyl; L³ is —N(R⁶); R⁵ is hydrogen, —CF₃, —CN,—COOH, —CONH₂, —CHF₂, —CH₂F, substituted or unsubstituted (C₁-C₅) alkyl,or substituted or unsubstituted 2 to 5 membered heteroalkyl; and R⁶ ishydrogen, —CF₃, —CN, —COOH, —CONH₂, —CHF₂, —CH₂F, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.
 2. The compound of claim 1, wherein Ring A issubstituted or unsubstituted (C₆-C₁₀) aryl or substituted orunsubstituted 5 to 10 membered heteroaryl.
 3. The compound of claim 2,wherein Ring A is R³-substituted or unsubstituted (C₆-C₁₀) aryl orR³-substituted or unsubstituted 5 to 10 membered heteroaryl; R³ isindependently hydrogen, halogen, —CX₃, —CN, —SO_(n)R¹⁰, —SO_(v)NR⁷R⁸,—NHNR⁷R⁸, —ONR⁷R⁸, —NHC═(O)NHNR⁷R⁸, —NHC═(O)NR′R⁸, —N(O)_(m), —NR⁷R⁸,—C(O)R⁹, —C(O)—OR⁹, —C(O)NR⁷R⁸, —OR¹⁰, —NR⁷SO₂R¹⁰, —NR⁷C═(O)R⁹,—NR⁷C(O)OR⁹, —NR⁷OR⁹, —CHX₂, —CH₂X, —OCX₃, —OCHX₂, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; Two adjacent R³ substituents may optionally bejoined to form a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁷, R⁸, R⁹, and R¹⁰ areindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃,—OCHF₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R⁷ and R⁸ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; m and v are independently 1 or 2; n is independently aninteger from 0 to 4; and X is independently —Cl, —Br, —I, or —F.
 4. Thecompound of claim 3, wherein Ring A is R³-substituted or unsubstitutedphenyl.
 5. The compound of claim 3, wherein R³ is independentlyhydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂,substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl.
 6. The compound of claim 1,having the formula:

wherein R³ is halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂,substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl.
 7. The compound of claim 1,having the formula:

wherein R^(3A), R^(3B), and R^(3C) are independently halogen, CF₃, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted or unsubstituted (C₁-C₅) alkyl,or substituted or unsubstituted 2 to 5 membered heteroalkyl; R^(3D) ishydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, —OCF₃, —OCHF₂,substituted or unsubstituted (C₁-C₅) alkyl, or substituted orunsubstituted 2 to 5 membered heteroalkyl; R^(3E) is hydrogen halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, or substituted or unsubstituted 2 to 5membered heteroalkyl.
 8. The compound of claim 7, wherein R^(3D) andR^(3E) are independently unsubstituted (C₁-C₃) alkyl.
 9. The compound ofclaim 7, wherein R^(3D) and R^(3E) are independently unsubstitutedmethyl.
 10. The compound of claim 7, having the formula:


11. The compound of claim 1, wherein Ring B is substituted orunsubstituted (C₃-C₁₀) cycloalkyl or substituted or unsubstituted 3 to10 membered heterocycloalkyl, substituted or unsubstituted (C₆-C₁₀)aryl, or substituted or unsubstituted 5 to 10 membered heteroaryl. 12.The compound of claim 11, wherein Ring B is R⁴-substituted orunsubstituted (C₃-C₁₀) cycloalkyl, R⁴-substituted or unsubstituted 5 to10 membered heterocycloalkyl, R⁴-substituted or unsubstituted (C₆-C₁₀)aryl, or R⁴-substituted or unsubstituted 5 to 10 membered heteroaryl; R⁴is independently oxo, halogen, —CX^(a) ₃, —CN, —SO_(n1)R¹⁴,—SO_(v1)NR¹¹R¹², —NHNR¹¹R¹², —ONR¹¹R¹², —NHC═(O)NHNR¹¹R¹²,—NHC═(O)NR¹¹R¹², —N(O)_(m1), —NR¹¹R¹², —C(O)R¹³, C(O) —OR¹³,—C(O)NR¹¹R¹², —OR¹⁴, —NR¹¹SO₂R¹⁴, —NR¹¹C═(O)R¹³, —NR¹¹C(O)OR¹³,—NR¹¹OR¹³, —CHX², —CH₂X, —OCX₃, —OCHX₂, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl; two adjacent R⁴ substituents may optionally be joined toform a substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹, R¹², R¹³, and R¹⁴ areindependently hydrogen, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —CHF₂, —CH₂F, —OCF₃,—OCHF₂, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R¹¹ and R¹² substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl or substituted or unsubstitutedheteroaryl; m1 and v1 are independently 1 or 2; n1 is independently aninteger from 0 to 4; and X^(a) is independently —Cl, —Br, —I, or —F. 13.The compound of claim 12, wherein Ring B is R⁴-substituted orunsubstituted thienyl, R⁴-substituted or unsubstituted phenyl,R⁴-substituted or unsubstituted benzothienyl, R⁴-substituted orunsubstituted naphthyl, R⁴-substituted or unsubstituted benzofuranyl,R⁴-substituted or unsubstituted furanyl, R⁴-substituted or unsubstitutedpyrrolyl, or R⁴-substituted or unsubstituted 2,3-dihydro-1H-indenyl. 14.The compound of claim 1, wherein Ring A is unsubstituted phenyl and RingB is unsubstituted thienyl; Ring A is para-hydroxy substituted phenyland Ring B is unsubstituted thienyl; Ring A is para-hydroxy substitutedphenyl and Ring B is unsubstituted phenyl; Ring A is para-hydroxysubstituted phenyl and Ring B is unsubstituted benzothienyl; Ring A ispara-hydroxy substituted phenyl and Ring B is para-methyl substitutedphenyl; Ring A is 2-hydroxy pyridin-4-yl and Ring B is unsubstitutedthienyl; Ring A is 2-hydroxy pyridin-5-yl and Ring B is unsubstitutedthienyl; Ring A is para-hydroxy substituted phenyl and Ring B isunsubstituted napththyl; or Ring A is para-hydroxy substituted phenyland Ring B is unsubstituted 2,3-dihydro-1H-indenyl.
 15. The compound ofclaim 11, wherein Ring B is unsubstituted phenyl. 16-17. (canceled) 18.The compound of claim 1, wherein R¹ is unsubstituted (C₁-C₂) alkyl. 19.The compound of claim 1, wherein R1 is independently hydrogen, halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl. 20.The compound of claim 1, wherein R² is unsubstituted (C₁-C₂) alkyl. 21.The compound of claim 1, wherein R² is independently hydrogen, halogen,—CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, substituted orunsubstituted (C₁-C₅) alkyl, substituted or unsubstituted 2 to 5membered heteroalkyl, substituted or unsubstituted (C₃-C₆) cycloalkyl,or substituted or unsubstituted 3 to 6 membered heterocycloalkyl. 22.The compound of claim 1, wherein R¹ and R² are joined to form asubstituted or unsubstituted 3 to 6 membered heterocycloalkyl orsubstituted or unsubstituted 5 to 6 membered heteroaryl.
 23. Thecompound of claim 1, wherein R⁵ is hydrogen, substituted orunsubstituted (C₁-C₅) alkyl or substituted or unsubstituted 2 to 5membered heteroalkyl.
 24. The compound of claim 1, wherein W is O. 25.(canceled)
 26. The compound of claim 1, wherein R⁶ is hydrogen,substituted or unsubstituted (C₁-C₅) alkyl or substituted orunsubstituted 2 to 5 membered heteroalkyl.
 27. The compound of claim 1,wherein L² is unsubstituted (C₁-C₃) alkylene.
 28. The compound of claim1, having the formula:

wherein d is an integer between 0 and
 3. 29. The compound of claim 1,having the formula:

wherein d is an integer between 0 and
 3. 30. The compound of claim 1,having the formula:

wherein: Ring B is a substituted or unsubstituted phenyl or substitutedor unsubstituted 5 to 6 membered heteroaryl; R³ is halogen, —OH, or—NH₂; R^(99a) is substituted or unsubstituted (C₁-C₃) alkyl; and R^(99b)is hydrogen or substituted or unsubstituted (C₁-C₃) alkyl.
 31. Thecompound of claim 30, wherein Ring B is an unsubstituted 3-thienyl. 32.The compound of claim 1, having the formula:

wherein: Ring B is a substituted or unsubstituted phenyl or substitutedor unsubstituted 5 to 6 membered heteroaryl; R^(3A) is halogen, —OH, or—NH₂; R^(3D) is unsubstituted (C₁-C₂) alkyl; R^(3E) is unsubstituted(C₁-C₂) alkyl; R^(99a) is hydrogen or substituted or unsubstituted(C₁-C₃) alkyl; R^(99b) is substituted or unsubstituted (C₁-C₃) alkyl.33. The compound of claim 1, having the formula:


34. The compound of claim 1, having the formula:


35. (canceled)
 36. A compound of claim 1, having a higher bindingaffinity for the mu opioid receptor than for the kappa opioid receptor.37. A compound of claim 1, having a higher binding affinity for the muopioid receptor than for the delta opioid receptor.
 38. A compound ofclaim 1, having a higher binding affinity for the mu opioid receptorthan for the nociceptin receptor.
 39. A compound of claim 1, having alower addiction potential than other medically used opioids or opiates.40. A compound of claim 1, having a lower addiction potential thanmorphine, heroin, oxycodone, fentanyl, hydrocodone, hydromorphone,methadone, or oxymorphone.
 41. A pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of claim
 1. 42. Amethod of treating pain in a subject in need of said treatment, saidmethod comprising administering an effective amount of a compound ofclaim 1 to said subject.
 43. The method of claim 42, wherein said methoddoes not comprise an increased risk of respiratory depression orconstipation.
 44. A method of treating opioid overdose in a subject inneed of said treatment, said method comprising administering aneffective amount of a compound of claim 1 to said subject.
 45. A methodof treating addiction in a subject in need of said treatment, saidmethod comprising administering an effective amount of a compound ofclaim 1, to said subject.
 46. A method of treating a psychiatricdisorder in a subject in need of said treatment, said method comprisingadministering an effective amount of a compound of claim 1 to saidsubject.
 47. A method of modulating the activity of an opioid receptorprotein, said method comprising contacting said opioid receptor proteinwith an effective amount of a compound of claim
 1. 48. The method ofclaim 47, wherein said method does not comprise modulating arrestinfunction.